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DEVELOPING METHODS FOR CRYSTALLIZING CLASS B GPCRS

Award Number: R43GM088950
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2009
PERIOD OF PERFORMANCE END DATE: 01/31/2010

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DEVELOPING METHODS FOR CRYSTALLIZING CLASS B GPCRS - DESCRIPTION (provided by applicant): G-protein-coupled receptors (GPCRs) represent the largest group of targets for drug discovery. Drug development for these receptors has relied heavily on high-throughput screening of large libraries of compounds. This strategy has seen some successes for a number of receptors, particularly Class A (rhodopsin family) GPCRs for non-peptide hormones and neurotransmitters. However, this approach has been mostly unsuccessful for Class B GPCRs. In this subfamily, the endogenous ligands are all relatively large peptides ranging in size from 27 to 84 amino acids. Class B GPCRs are characterized by an extended ligand recognition surface that includes residues from the transmembrane domains, from the large N- terminal domain, and from the interhelical extracellular segments. This extended ligand recognition surface likely explains the difficulty in developing small molecule drugs selective for Class B GPCRs. Alternative or complementary approaches thus need to be developed that include high-resolution structural information, which can in turn be used to design drugs based on the receptor structure. At present, only a handful of GPCR structures have been solved, and none within the Class B GPCR subfamily. A recent advance in crystallization technology, generating GPCR-T4 Lysozyme (GPCR-T4L) fusion proteins, has led to high-resolution structures of two Class A GPCRs, opening new opportunities for structure-based design of drugs. ConfometRx has obtained the exclusive licensing rights for the commercial application of GPCR-T4L technology, which was developed in Brian Kobilka's lab at Stanford University. We propose here to adapt this technology to Class B receptors. In phase I of this SBIR, we aim to determine the feasibility of using the GPCR-T4L technology to express and purify a functional T4L fusion receptor for a selected Class B GPCR. In phase II, we will proceed with the crystallization trials and structure determination. In addition, once the methodology developed here is established, it will be applied to other Class B GPCRs. The structural information collected with this approach could become a critical component for the successful development of new small molecule drugs. PUBLIC HEALTH RELEVANCE: In this SBIR, we propose to determine the three-dimensional structure of a receptor that belongs to an important family of drug targets, the Class B family of G-protein-coupled receptors. They participate in the physiological regulation of metabolism and growth, and in immuno/neuro-modulations as well as endocrine/exocrine secretions, but drug development targeted at these receptors has been mostly unsuccessful. By solving the structure of such a receptor, we hope to provide a critical tool for the development of new drugs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2009 ( Subtotal = $100,000 )
2009	2009	CONFOMETRX INC	840 CHIMALUS DRIVE	PALO ALTO	CA	94306	SANTA CLARA	USA	Biomedical Research and Research Training	001	1	7/30/2009	NEW	$0
2009	2009	CONFOMETRX INC	840 CHIMALUS DRIVE	PALO ALTO	CA	94306	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	7/27/2009	NEW	$100,000
														Subtotal = $100,000

Grand Total All Awards = $100,000

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DEVELOPING METHODS FOR CRYSTALLIZING CLASS B GPCRS

Award Number: R43GM088950

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2009

PERIOD OF PERFORMANCE END DATE: 01/31/2010

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