Structural Biology (Maier)Head of Research Unit Prof. Dr.Timm MaierOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 22 foundShow per page10 10 20 50 Unlocking mTORC2: Mechanisms of localized mTORC2 activation (mTORC2.Act) Research Project | 2 Project MembersImported from Grants Tool 4700751 The Architecture of Microbial Biosynthetic Assembly Lines Research Project | 1 Project MembersNo Description available Preclinical in vivo proof of mechanism study of selective mTORC1 inhibitors Research Project | 2 Project MembersLaufzeit 01.04.2022-31.01.2024 Increased activity of mammalian target of rapamycin complex 1(mTORC1) is linked to multiple disorders. We identified ten small compounds that selectively and efficiently inhibit mTORC1 in vitro with an innovative mode of action. We now aim to achieve precinlincal proof of mechanism in mice. HPDET-EM - Novel detectors for cryo electron microscopy Research Project | 4 Project Memberszu ergänzen Building the master controller of proliferation: Assembly of mTOR complexes Research Project | 2 Project MembersThe protein kinase mammalian target of rapamycin (mTOR) is the master regulator of eukaryotic cell growth and proliferation. It exerts its functions via two different multiprotein complexes, which integrate cellular growth-factor signaling, nutrient availability and stress to control the switch between catabolism and anabolism, proliferation and survival. mTOR is the founding member of the PI3K-related kinase (PIKK) family, which includes five other structurally and functionally diverse kinases linked to central DNA and RNA quality control systems. Despite emerging insights into signaling events of mTOR and other PIKKs, the assembly of their active complexes through a conserved chaperone system remains poorly characterized. My PhD project aims at the characterization of mTOR (and PIKK) folding and complex assembly and its implications in eukaryotic cellular signaling in health and disease. The specific recognition of mTOR by its chaperone complex will be examined primarily through cryo-electron microscopy in combination with biophysical studies. Biochemical in vitro and cellular experiments will provide crucial insights into the mechanism of PIKK folding, complex assembly and release from the assembly machinery. Links between mechanisms of mTOR complex assembly and human disease will be investigated via multi-omics data and potentially provide novel therapeutic approaches. Structural and functional characterization of P-Rex 1/2 in cell signaling and cancer Research Project | 2 Project MembersPhosphatidyl-inositol 3,4,5 triphosphoshate-dependent Rac exchanger (P-Rex) are a group of proteins involved in the activation of the small GTPase Rac, by acting as a guanidine exchange factor (GEF). Both Rac and P-Rex proteins are known to be overexpressed and altered in several cancers, consistent with their role in both cell mobility and their numerous interactions with both the mTOR axis and the PI3K/PTEN pathway. P-Rex1/2 specifically, are known to interact with mTOR and PTEN, among others, placing them at the nexus of regulatory pathways for cell metabolism, proliferation and mobility.Despite their central role in cell signaling, very little is known about the interplay between such interactions. No structural information is available for the full-length P-Rex proteins and how different interaction partners affect its structure and function. I will therefore set out to better characterize the emerging properties of the multidomain P-Rex proteins by purifying both P-Rex1/2 and determining their structure using cryo-EM and orthogonal biophysical characterization methods. I then aim to define the interaction between P-Rex proteins and its regulatory partners, PTEN and the mTOR complexes 1 and 2. I will define their domains of interactions and determine the structure of the complexes, using a combination of cryo-EM and cross-linking and mass-spectrometry. We expect to provide new insights into the functions of P-Rex proteins and their crosstalk with core cellular signaling pathways. Structures of full-lengths P-Rex alone or in complex with its interaction partners will serve as a platform for drug discovery, thereby providing new cancer therapeutic avenues In search of an anti-aging drug: Selective mTORC1 inhibition Research Project | 2 Project MembersAge is the major risk factor for many chronic disorders such as heart disease, arthritis, cancer and dementia. Given the global aging of the population, developing interventions that preserve health in old age and delay the onset of age-related diseases is of utmost relevance. However, developing new strategies to delay aging is a risky, time consuming, and expensive endeavor. The target of rapamycin complex 1 (TORC1) signaling pathway drives organismal aging and its inhibition is a leading candidate for targeting aging. However, long term clinical use of currently available TORC1 inhibitors is limited due to undesirable off-target effects such as hyperglycemia, hyperlipidemia, and insulin resistance. Thus, the ability to selectively inhibit TORC1 uncovers a high therapeutic potential for age-related diseases. We aim to explore a novel mode of TORC1 inhibition for anti-aging applications. The results could be used to develop a novel class of anti-aging drugs that delay the onset and progression of age-related diseases generating unprecedented health benefits. Assembly Lines for Biocombinatorial Chemistry AL4BIOCH Research Project | 2 Project MembersPolyketide Synthases (PKS) are biological factories for the production of potent natural products, including antibiotics, anti‐cancer drugs, statins and further drugs. The exceptional chemical diversity generated by PKS is encoded in their modular architecture. The domains required for one step of precursor elongation and modification are combined into a functional polypeptide module. PKS modules can either act iteratively (iPKS) or in a linearly organized assembly line of multiple modules (modPKS). The collinearity between synthesis and protein sequence in modPKS promised the opportunity for rational re‐engineering of PKS at the genetic level in order to produce novel compounds. However, information on functional protein-protein interactions and substrate transfer in PKS beyond the level of isolated domains is sparse and divergent architectural models of module organization have been proposed. In the AL4BIOCH project, we aim to reveal the fundamental intermodular assembly line organization underlying the unique biosynthetic generation of chemical diversity by modPKS. For this purpose, we employ cryo-electron microscopy to comprehensively study the organization of modPKS bimodules as minimal representations of assembly lines organization. In combination with functional analysis, biophysical studies and chemoenzymatic trapping we address the architectures underlying directed substrate transfer. The research builds on modern and rapidly evolving techniques, including cryo electron microscopy, advanced optical imaging and biophysics, as well as chemical probes, which are most relevant for front-line molecular biology research. Success in this project will allow the host lab and organization to establish new collaborations for translating insights on modPKS architecture for the design of novel or re-engineered assembly lines for the generation of advanced chemical compounds and drug candidates. Structural and functional characterization of P-Rex 1/2 in cell signaling and cancer Research Project | 2 Project MembersNo Description available Feasibility study: Development of a lead compound for specific mTORC1 inhibition Research Project | 4 Project MembersmTORC1 is a master regulator of cell growth and metabolism. mTORC1 is an important pharmacological target as its deregulation is implicated in multiple diseases. However, the clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives) is limited by their specificity, effectiveness, and safety. Chronic and systemic administration of current mTORC1 inhibitors is often associated with undesirable side effects on metabolism, including hyperglycemia, hyperlipidemia, and insulin resistance. This hinders the use of mTORC1 inhibition as a pharmacologic strategy to treat multiple conditions with unmet therapeutic needs. They include cancer, epilepsy, depression, autism and stroke, obesity and diabetes, autoimmunity, age-related pathologies. We aim to generate a lead compound that justifies its further development into a drug to treat diseases arising from unbridled mTORC1 activity. Initially, we intend to focus on the lifelong tumor syndrome TSC (tuberous sclerosis complex) and, in the long term, to other conditions mentioned above. mTORC1 substrate recruitment is an unexplored pharmacological target. We provided a structural basis for analyzing this process. Based on this study, we established a biophysical assay to identify novel compounds that block mTORC1 substrate recruitment. We expect such compounds to be more specific, effective and safer than the currently available mTORC1 inhibitors, possibly allowing for higher dose or prolonged treatment. The clinical potential of these novel compounds would be immense and readily testable. This project displays a considerable innovation potential. It involves an experienced, highly committed, and cross-disciplinary team at the forefront of knowledge in the relevant fields. This project may form the basis for establishment of a start-up company in Switzerland to further develop the lead compound and bring it to clinical trials and to market. 123 123 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 22 foundShow per page10 10 20 50 Unlocking mTORC2: Mechanisms of localized mTORC2 activation (mTORC2.Act) Research Project | 2 Project MembersImported from Grants Tool 4700751 The Architecture of Microbial Biosynthetic Assembly Lines Research Project | 1 Project MembersNo Description available Preclinical in vivo proof of mechanism study of selective mTORC1 inhibitors Research Project | 2 Project MembersLaufzeit 01.04.2022-31.01.2024 Increased activity of mammalian target of rapamycin complex 1(mTORC1) is linked to multiple disorders. We identified ten small compounds that selectively and efficiently inhibit mTORC1 in vitro with an innovative mode of action. We now aim to achieve precinlincal proof of mechanism in mice. HPDET-EM - Novel detectors for cryo electron microscopy Research Project | 4 Project Memberszu ergänzen Building the master controller of proliferation: Assembly of mTOR complexes Research Project | 2 Project MembersThe protein kinase mammalian target of rapamycin (mTOR) is the master regulator of eukaryotic cell growth and proliferation. It exerts its functions via two different multiprotein complexes, which integrate cellular growth-factor signaling, nutrient availability and stress to control the switch between catabolism and anabolism, proliferation and survival. mTOR is the founding member of the PI3K-related kinase (PIKK) family, which includes five other structurally and functionally diverse kinases linked to central DNA and RNA quality control systems. Despite emerging insights into signaling events of mTOR and other PIKKs, the assembly of their active complexes through a conserved chaperone system remains poorly characterized. My PhD project aims at the characterization of mTOR (and PIKK) folding and complex assembly and its implications in eukaryotic cellular signaling in health and disease. The specific recognition of mTOR by its chaperone complex will be examined primarily through cryo-electron microscopy in combination with biophysical studies. Biochemical in vitro and cellular experiments will provide crucial insights into the mechanism of PIKK folding, complex assembly and release from the assembly machinery. Links between mechanisms of mTOR complex assembly and human disease will be investigated via multi-omics data and potentially provide novel therapeutic approaches. Structural and functional characterization of P-Rex 1/2 in cell signaling and cancer Research Project | 2 Project MembersPhosphatidyl-inositol 3,4,5 triphosphoshate-dependent Rac exchanger (P-Rex) are a group of proteins involved in the activation of the small GTPase Rac, by acting as a guanidine exchange factor (GEF). Both Rac and P-Rex proteins are known to be overexpressed and altered in several cancers, consistent with their role in both cell mobility and their numerous interactions with both the mTOR axis and the PI3K/PTEN pathway. P-Rex1/2 specifically, are known to interact with mTOR and PTEN, among others, placing them at the nexus of regulatory pathways for cell metabolism, proliferation and mobility.Despite their central role in cell signaling, very little is known about the interplay between such interactions. No structural information is available for the full-length P-Rex proteins and how different interaction partners affect its structure and function. I will therefore set out to better characterize the emerging properties of the multidomain P-Rex proteins by purifying both P-Rex1/2 and determining their structure using cryo-EM and orthogonal biophysical characterization methods. I then aim to define the interaction between P-Rex proteins and its regulatory partners, PTEN and the mTOR complexes 1 and 2. I will define their domains of interactions and determine the structure of the complexes, using a combination of cryo-EM and cross-linking and mass-spectrometry. We expect to provide new insights into the functions of P-Rex proteins and their crosstalk with core cellular signaling pathways. Structures of full-lengths P-Rex alone or in complex with its interaction partners will serve as a platform for drug discovery, thereby providing new cancer therapeutic avenues In search of an anti-aging drug: Selective mTORC1 inhibition Research Project | 2 Project MembersAge is the major risk factor for many chronic disorders such as heart disease, arthritis, cancer and dementia. Given the global aging of the population, developing interventions that preserve health in old age and delay the onset of age-related diseases is of utmost relevance. However, developing new strategies to delay aging is a risky, time consuming, and expensive endeavor. The target of rapamycin complex 1 (TORC1) signaling pathway drives organismal aging and its inhibition is a leading candidate for targeting aging. However, long term clinical use of currently available TORC1 inhibitors is limited due to undesirable off-target effects such as hyperglycemia, hyperlipidemia, and insulin resistance. Thus, the ability to selectively inhibit TORC1 uncovers a high therapeutic potential for age-related diseases. We aim to explore a novel mode of TORC1 inhibition for anti-aging applications. The results could be used to develop a novel class of anti-aging drugs that delay the onset and progression of age-related diseases generating unprecedented health benefits. Assembly Lines for Biocombinatorial Chemistry AL4BIOCH Research Project | 2 Project MembersPolyketide Synthases (PKS) are biological factories for the production of potent natural products, including antibiotics, anti‐cancer drugs, statins and further drugs. The exceptional chemical diversity generated by PKS is encoded in their modular architecture. The domains required for one step of precursor elongation and modification are combined into a functional polypeptide module. PKS modules can either act iteratively (iPKS) or in a linearly organized assembly line of multiple modules (modPKS). The collinearity between synthesis and protein sequence in modPKS promised the opportunity for rational re‐engineering of PKS at the genetic level in order to produce novel compounds. However, information on functional protein-protein interactions and substrate transfer in PKS beyond the level of isolated domains is sparse and divergent architectural models of module organization have been proposed. In the AL4BIOCH project, we aim to reveal the fundamental intermodular assembly line organization underlying the unique biosynthetic generation of chemical diversity by modPKS. For this purpose, we employ cryo-electron microscopy to comprehensively study the organization of modPKS bimodules as minimal representations of assembly lines organization. In combination with functional analysis, biophysical studies and chemoenzymatic trapping we address the architectures underlying directed substrate transfer. The research builds on modern and rapidly evolving techniques, including cryo electron microscopy, advanced optical imaging and biophysics, as well as chemical probes, which are most relevant for front-line molecular biology research. Success in this project will allow the host lab and organization to establish new collaborations for translating insights on modPKS architecture for the design of novel or re-engineered assembly lines for the generation of advanced chemical compounds and drug candidates. Structural and functional characterization of P-Rex 1/2 in cell signaling and cancer Research Project | 2 Project MembersNo Description available Feasibility study: Development of a lead compound for specific mTORC1 inhibition Research Project | 4 Project MembersmTORC1 is a master regulator of cell growth and metabolism. mTORC1 is an important pharmacological target as its deregulation is implicated in multiple diseases. However, the clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives) is limited by their specificity, effectiveness, and safety. Chronic and systemic administration of current mTORC1 inhibitors is often associated with undesirable side effects on metabolism, including hyperglycemia, hyperlipidemia, and insulin resistance. This hinders the use of mTORC1 inhibition as a pharmacologic strategy to treat multiple conditions with unmet therapeutic needs. They include cancer, epilepsy, depression, autism and stroke, obesity and diabetes, autoimmunity, age-related pathologies. We aim to generate a lead compound that justifies its further development into a drug to treat diseases arising from unbridled mTORC1 activity. Initially, we intend to focus on the lifelong tumor syndrome TSC (tuberous sclerosis complex) and, in the long term, to other conditions mentioned above. mTORC1 substrate recruitment is an unexplored pharmacological target. We provided a structural basis for analyzing this process. Based on this study, we established a biophysical assay to identify novel compounds that block mTORC1 substrate recruitment. We expect such compounds to be more specific, effective and safer than the currently available mTORC1 inhibitors, possibly allowing for higher dose or prolonged treatment. The clinical potential of these novel compounds would be immense and readily testable. This project displays a considerable innovation potential. It involves an experienced, highly committed, and cross-disciplinary team at the forefront of knowledge in the relevant fields. This project may form the basis for establishment of a start-up company in Switzerland to further develop the lead compound and bring it to clinical trials and to market. 123 123
Unlocking mTORC2: Mechanisms of localized mTORC2 activation (mTORC2.Act) Research Project | 2 Project MembersImported from Grants Tool 4700751
The Architecture of Microbial Biosynthetic Assembly Lines Research Project | 1 Project MembersNo Description available
Preclinical in vivo proof of mechanism study of selective mTORC1 inhibitors Research Project | 2 Project MembersLaufzeit 01.04.2022-31.01.2024 Increased activity of mammalian target of rapamycin complex 1(mTORC1) is linked to multiple disorders. We identified ten small compounds that selectively and efficiently inhibit mTORC1 in vitro with an innovative mode of action. We now aim to achieve precinlincal proof of mechanism in mice.
HPDET-EM - Novel detectors for cryo electron microscopy Research Project | 4 Project Memberszu ergänzen
Building the master controller of proliferation: Assembly of mTOR complexes Research Project | 2 Project MembersThe protein kinase mammalian target of rapamycin (mTOR) is the master regulator of eukaryotic cell growth and proliferation. It exerts its functions via two different multiprotein complexes, which integrate cellular growth-factor signaling, nutrient availability and stress to control the switch between catabolism and anabolism, proliferation and survival. mTOR is the founding member of the PI3K-related kinase (PIKK) family, which includes five other structurally and functionally diverse kinases linked to central DNA and RNA quality control systems. Despite emerging insights into signaling events of mTOR and other PIKKs, the assembly of their active complexes through a conserved chaperone system remains poorly characterized. My PhD project aims at the characterization of mTOR (and PIKK) folding and complex assembly and its implications in eukaryotic cellular signaling in health and disease. The specific recognition of mTOR by its chaperone complex will be examined primarily through cryo-electron microscopy in combination with biophysical studies. Biochemical in vitro and cellular experiments will provide crucial insights into the mechanism of PIKK folding, complex assembly and release from the assembly machinery. Links between mechanisms of mTOR complex assembly and human disease will be investigated via multi-omics data and potentially provide novel therapeutic approaches.
Structural and functional characterization of P-Rex 1/2 in cell signaling and cancer Research Project | 2 Project MembersPhosphatidyl-inositol 3,4,5 triphosphoshate-dependent Rac exchanger (P-Rex) are a group of proteins involved in the activation of the small GTPase Rac, by acting as a guanidine exchange factor (GEF). Both Rac and P-Rex proteins are known to be overexpressed and altered in several cancers, consistent with their role in both cell mobility and their numerous interactions with both the mTOR axis and the PI3K/PTEN pathway. P-Rex1/2 specifically, are known to interact with mTOR and PTEN, among others, placing them at the nexus of regulatory pathways for cell metabolism, proliferation and mobility.Despite their central role in cell signaling, very little is known about the interplay between such interactions. No structural information is available for the full-length P-Rex proteins and how different interaction partners affect its structure and function. I will therefore set out to better characterize the emerging properties of the multidomain P-Rex proteins by purifying both P-Rex1/2 and determining their structure using cryo-EM and orthogonal biophysical characterization methods. I then aim to define the interaction between P-Rex proteins and its regulatory partners, PTEN and the mTOR complexes 1 and 2. I will define their domains of interactions and determine the structure of the complexes, using a combination of cryo-EM and cross-linking and mass-spectrometry. We expect to provide new insights into the functions of P-Rex proteins and their crosstalk with core cellular signaling pathways. Structures of full-lengths P-Rex alone or in complex with its interaction partners will serve as a platform for drug discovery, thereby providing new cancer therapeutic avenues
In search of an anti-aging drug: Selective mTORC1 inhibition Research Project | 2 Project MembersAge is the major risk factor for many chronic disorders such as heart disease, arthritis, cancer and dementia. Given the global aging of the population, developing interventions that preserve health in old age and delay the onset of age-related diseases is of utmost relevance. However, developing new strategies to delay aging is a risky, time consuming, and expensive endeavor. The target of rapamycin complex 1 (TORC1) signaling pathway drives organismal aging and its inhibition is a leading candidate for targeting aging. However, long term clinical use of currently available TORC1 inhibitors is limited due to undesirable off-target effects such as hyperglycemia, hyperlipidemia, and insulin resistance. Thus, the ability to selectively inhibit TORC1 uncovers a high therapeutic potential for age-related diseases. We aim to explore a novel mode of TORC1 inhibition for anti-aging applications. The results could be used to develop a novel class of anti-aging drugs that delay the onset and progression of age-related diseases generating unprecedented health benefits.
Assembly Lines for Biocombinatorial Chemistry AL4BIOCH Research Project | 2 Project MembersPolyketide Synthases (PKS) are biological factories for the production of potent natural products, including antibiotics, anti‐cancer drugs, statins and further drugs. The exceptional chemical diversity generated by PKS is encoded in their modular architecture. The domains required for one step of precursor elongation and modification are combined into a functional polypeptide module. PKS modules can either act iteratively (iPKS) or in a linearly organized assembly line of multiple modules (modPKS). The collinearity between synthesis and protein sequence in modPKS promised the opportunity for rational re‐engineering of PKS at the genetic level in order to produce novel compounds. However, information on functional protein-protein interactions and substrate transfer in PKS beyond the level of isolated domains is sparse and divergent architectural models of module organization have been proposed. In the AL4BIOCH project, we aim to reveal the fundamental intermodular assembly line organization underlying the unique biosynthetic generation of chemical diversity by modPKS. For this purpose, we employ cryo-electron microscopy to comprehensively study the organization of modPKS bimodules as minimal representations of assembly lines organization. In combination with functional analysis, biophysical studies and chemoenzymatic trapping we address the architectures underlying directed substrate transfer. The research builds on modern and rapidly evolving techniques, including cryo electron microscopy, advanced optical imaging and biophysics, as well as chemical probes, which are most relevant for front-line molecular biology research. Success in this project will allow the host lab and organization to establish new collaborations for translating insights on modPKS architecture for the design of novel or re-engineered assembly lines for the generation of advanced chemical compounds and drug candidates.
Structural and functional characterization of P-Rex 1/2 in cell signaling and cancer Research Project | 2 Project MembersNo Description available
Feasibility study: Development of a lead compound for specific mTORC1 inhibition Research Project | 4 Project MembersmTORC1 is a master regulator of cell growth and metabolism. mTORC1 is an important pharmacological target as its deregulation is implicated in multiple diseases. However, the clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives) is limited by their specificity, effectiveness, and safety. Chronic and systemic administration of current mTORC1 inhibitors is often associated with undesirable side effects on metabolism, including hyperglycemia, hyperlipidemia, and insulin resistance. This hinders the use of mTORC1 inhibition as a pharmacologic strategy to treat multiple conditions with unmet therapeutic needs. They include cancer, epilepsy, depression, autism and stroke, obesity and diabetes, autoimmunity, age-related pathologies. We aim to generate a lead compound that justifies its further development into a drug to treat diseases arising from unbridled mTORC1 activity. Initially, we intend to focus on the lifelong tumor syndrome TSC (tuberous sclerosis complex) and, in the long term, to other conditions mentioned above. mTORC1 substrate recruitment is an unexplored pharmacological target. We provided a structural basis for analyzing this process. Based on this study, we established a biophysical assay to identify novel compounds that block mTORC1 substrate recruitment. We expect such compounds to be more specific, effective and safer than the currently available mTORC1 inhibitors, possibly allowing for higher dose or prolonged treatment. The clinical potential of these novel compounds would be immense and readily testable. This project displays a considerable innovation potential. It involves an experienced, highly committed, and cross-disciplinary team at the forefront of knowledge in the relevant fields. This project may form the basis for establishment of a start-up company in Switzerland to further develop the lead compound and bring it to clinical trials and to market.
