G protein-coupled receptors (GPCRs) are the largest family of integral membrane proteins that occur in nearly every eukaryotic cell to transduce an extracellular signal (ligand binding) into an intracellular signal (G protein activation). This essential physiological role makes them the most important pharmaceutical targets which comprise approximately half of today's modern medicinal drugs. Clearly, 3D-structures of GPCRs would provide essential atomic-level information for elucidating the molecular organization and for efficient virtual screening of drug databases. However, except for the recently solved human beta2-andrenergic receptor, it has not yet been possible to obtain experimental structural information for other human GPCRs. Building on the recent success of the threading assemble refinement (TASSER) algorithm for reduced-level GPCR modeling, this proposal seeks to develop new computational methodologies for the generation of experiment- validated, atomic-level GPCR models. The focus will be on five pharmaceutically important families including Adrenergic, Chemokine, Dopamine, Histamine, and Muscarinic acetylcholine.
Specific aims of the project are: (1) Development and benchmarking of a new GPCR-TASSER algorithm for atomic-level GPCR protein structure modeling. (2) Development and optimization of composite atomic and reduced GPCR potentials. (3) Dissemination of GPCR-TASSER algorithm for public use and examination. (4) Application of GPCR-TASSER to the pharmaceutically important GPCRs. (5) Validation and refinement of the GPCR models with experiment collaborators. The long-term goals are (a) to develop a set of computer algorithms for automated and atomic- level GPCR structure prediction (b) to extend the methodology to proteomic-scale structure modeling for all GPCRs in UniProt database (c) to construct a central repository for publicly-accessible GPCR algorithms and structure databases which are designed to eventually alleviate the urgent need in biology and medical communities for the detailed atomic GPCR structures.

Public Health Relevance

In modern structure-based drug design, scientists use detailed knowledge of the 3-dimensional structure of protein targets associated with particular diseases to design synthetic compounds that fight the disease. More than half of all drug targets are G protein-coupled receptors (GPCRs), a family of proteins whose structures are extremely difficult to obtain by experiment. The development of computer-based algorithms that are able to generate high resolution GPCR structures will speed up the initial screening of putative chemical compounds and therefore have an important impact on the field of the new drug discovery and public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084222-05
Application #
8233525
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Chin, Jean
Project Start
2009-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$315,855
Indirect Cost
$70,830
Name
University of Michigan Ann Arbor
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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