2BV1

Regulator of G-protein Signalling 1 (Human)

Summary for 2BV1

• Entry DOI: 10.2210/pdb2bv1/pdb
• Descriptor: REGULATOR OF G-PROTEIN SIGNALLING 1 (2 entities in total)
• Functional Keywords: rgs1, rgs, g-protein, regulator, structural genomics, structural genomics consortium, b-cell activation, phosphorylation, signal transduction inhibitor, signaling protein
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane ; Peripheral membrane protein ; Cytoplasmic side : Q08116
• Total number of polymer chains: 2
• Total formula weight: 33151.59

Authors

Elkins, J.M.,Yang, X.,Soundararajan, M.,Schoch, G.A.,Haroniti, A.,Sundstrom, M.,Edwards, A.,Arrowsmith, C.,Doyle, D.A. (deposition date: 2005-06-20, release date: 2005-06-27, Last modification date: 2023-12-13)

Primary citation

Soundararajan, M.,Willard, F.S.,Kimple, A.J.,Turnbull, A.P.,Ball, L.J.,Schoch, G.A.,Gileadi, C.,Fedorov, O.Y.,Dowler, E.F.,Higman, V.A.,Hutsell, S.Q.,Sundstrom, M.,Doyle, D.A.,Siderovski, D.P.
Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits.
Proc. Natl. Acad. Sci. U.S.A., 105:6457-6462, 2008

PubMed Abstract: Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Galpha subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs-receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with Galpha when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of Galpha, RGS domain binding consequently accelerates Galpha-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied Galpha substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their differential Galpha selectivities. Here, we determined 14 structures derived from NMR and x-ray crystallography of members of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed RGS domains and 4 RGS domain/Galpha complexes. Heterogeneity observed in the structural architecture of the RGS domain, as well as in engagement of switch III and the all-helical domain of the Galpha substrate, suggests that unique structural determinants specific to particular RGS protein/Galpha pairings exist and could be used to achieve selective inhibition by small molecules.

PubMed: 18434541
DOI: 10.1073/pnas.0801508105

Experimental method

X-RAY DIFFRACTION (2 Å)