|
|
||||||
|
|
||||||
|
Dr. Soo-Kyung Kim, NIDDK
Friday,
Dec.
16, 2005 GPCR Networks in Drug Discovery
Abstract: A3 adenosine receptors (AR) belong to the rhodopsin family A G-Protein Coupled Receptor (GPCRs). A3AR agonists may have potential as cardioprotective and cerebroprotective agents, for the treatment of asthma, as anti-inflammatory and immunosuppressive agents, and in cancer therapy as cytostatics and chemoprotective compounds. Molecular modeling was used to understand GPCR networks; (1) the mechanism of agonist interactions with GPCRs, (2) the GPCR dimerization which was important in the development of GPCR-targeted drugs, and (3) the active role of phopholipid in biological membrane. A three-dimensional model of the human A3AR was built by homology using the x-ray structure of rhodopsin as a template. Recently, more reliable 3D structure of the A3AR, using MD in a fully hydrated lipid bilayer environment was generated. A3 selective nucleoside agonists and nucleoside/non-nucleoside antagonists were docked using FlexX and FlexiDock automated docking procedures. Additional H-bonding of the ribose 3’- and 5’-substituents of agonist with hydrophilic amino acids T3.36, S7.42, and H7.43 and hydrophobic interaction of the terminal methyl group of the 5?-uronamide with the hydrophobic side chain of F6.44 disrupts the intramolecular H-bonding network involving conserved W6.48 and H7.42, following characteristic side-chain movements of TM6 and TM7. In addition, various transmembrane (TM) contact sites in homodimerization of the A3AR, namely TM1-2, TM2-3, TM2-4, TM3-4, TM4-5, TM5-6, TM6-7, and TM7-1, were created by a novel “fit-centroids-normal” method. The computational prediction clearly delineated the TM4-5 interface as leading to an energetically favorable homodimer and a high degree of shape complementarity at the TM surface contact area. These findings correlated well with the semi-empirical model of rhodopsin in the native disc membrane studied by atomic force microscopy. Considering that all class A GPCRs share a considerable degree of structural homology, it is likely that our results with the A3ARs are also relevant for other GPCRs, the largest protein family in the human genome.
Dr. Kim received her B.S. and M.S. in biochemistry from Chung-Nam National University (Taejon, Korea), and her Ph.D. in chemistry from Yonsei University (Seoul, Korea). Since 2001, she has been a postdoctoral fellow in the lab of Dr. Kenneth Jacobson. Dr. Kim's research focuses on computational modeling of G-protein coupled receptors and adenosine receptors. |
||||||
|
[IG Home] [Mtgs/Seminars] [Members] [Join the SIG] [Special Items] [Archives] |