G protein-coupled receptors sense an astonishing variety of extracellular molecular signals and trigger complex intracellular and physiological responses. They share a common architecture of seven transmembrane helices connected by a broad range of intra- and extra-cellular loops and terminal domains. Structure determination feasibility of this protein family was demonstrated recently with the first high resolution studies on the human Beta2 adrenergic, turkey Beta1 adrenergic, and human adenosine A2A receptors. The Center for Membrane Protein Structure Determination (CMPD) has been created to use a protein family specific platform to determine the high resolution structures of 15-20 representative GPCRs distributed across the phylogenetic tree. Receptor structures are needed at a biologically relevant granularity, for small molecule ligand receptors, peptide and protein receptors, lipid receptors, class B-F receptors, and of receptors in the active and inactive functional states. Each receptor structure will be determined with a set of different pharmacological ligands to define the receptor binding site(s). Solution studies will be conducted with purified receptors bound to different ligands to understand receptor dynamics using hydrogen-deuterium exchange and NMR spectroscopy. In collaboration with the NIH screening center, a library of small molecule probes will be used to analyze each receptor and discover allosteric binding sites using a high throughput thermal stability screen. Through a biologically informed selection of representative receptors, we will maximize the CMPD's impact through computational modeling of close homolog's and functional studies by external collaborators thereby establishing The PSI GPCR Network. The generated data will be provided to the community in a time frame consistent with the guidelines of the Protein Structure Initiative. Technology access will be achieved through on-site training, workshops, meetings, and publications. Processing access to the CMPD core facility will be provided through a 30% pipeline capacity commitment for the PSI: Biology Network nominated targets. Based on the experience of the CMPD investigators, preference will be for human or eukaryotic membrane proteins to maximally leverage the CMPD capabilities.
G-protein coupled receptors are the largest protein family in the human genome with more than 800 different members and the target for more than 50% of all therapeutic drugs. Genetic variation in the cell surface receptors result in the disruption of functions that are implicated in a wide variety of human diseases. Structural studies are necessary to understand the exquisite molecular recognition and signal transduction properties of this important protein family for both basic and applied biomedical research.
|Eddy, Matthew T; Didenko, Tatiana; Stevens, Raymond C et al. (2016) Î²2-Adrenergic Receptor Conformational Response to Fusion Protein in the Third Intracellular Loop. Structure 24:2190-2197|
|Rowe, Timothy B; Luo, Zhe-Xi; Ketcham, Richard A et al. (2016) X-ray computed tomography datasets for forensic analysis of vertebrate fossils. Sci Data 3:160040|
|Ngo, Tony; Kufareva, Irina; Coleman, James L J et al. (2016) Identifying ligands at orphan GPCRs: current status using structure-based approaches. Br J Pharmacol :|
|Kufareva, Irina; Gustavsson, Martin; Holden, Lauren G et al. (2016) Disulfide Trapping for Modeling and Structure Determination of Receptor: Chemokine Complexes. Methods Enzymol 570:389-420|
|Yang, Dehua; de Graaf, Chris; Yang, Linlin et al. (2016) Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R). J Biol Chem 291:12991-3004|
|Zheng, Yi; Qin, Ling; ZacarÃas, Natalia V Ortiz et al. (2016) Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540:458-461|
|Zhu, Lan; Weierstall, Uwe; Cherezov, Vadim et al. (2016) Serial Femtosecond Crystallography of Membrane Proteins. Adv Exp Med Biol 922:151-60|
|White, Thomas A; Barty, Anton; Liu, Wei et al. (2016) Serial femtosecond crystallography datasets from G protein-coupled receptors. Sci Data 3:160057|
|Batyuk, Alexander; Galli, Lorenzo; Ishchenko, Andrii et al. (2016) Native phasing of x-ray free-electron laser data for a G protein-coupled receptor. Sci Adv 2:e1600292|
|Leach, Katie; Gregory, Karen J; Kufareva, Irina et al. (2016) Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor. Cell Res 26:574-92|
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