PDBsum entry 2ode

Signaling protein

PDB id: 2ode

Contents

Protein chains

316 a.a. *

131 a.a. *

116 a.a. *

Ligands

ALF ×2

GDP ×2

Metals

_MG ×2

Waters ×655

* Residue conservation analysis

PDB id:

2ode

Name:

Signaling protein

Title:

Crystal structure of the heterodimeric complex of human rgs8 and activated gi alpha 3

Structure:

Guanine nucleotide-binding protein g(k) subunit alpha. Chain: a, c. Synonym: gi, alpha-3. Engineered: yes. Regulator of g-protein signaling 8. Chain: b, d. Fragment: residues 42-180. Synonym: rgs8. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gnai3. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: rgs8.

Resolution:

1.90Å R-factor: 0.181 R-free: 0.211

Authors:

C.Gileadi,M.Soundararajan,A.P.Turnbull,J.M.Elkins,E.Papagrigoriou, A.C.W.Pike,G.Bunkoczi,F.Gorrec,C.Umeano,F.Von Delft,J.Weigelt, A.Edwards,C.H.Arrowsmith,M.Sundstrom,D.A.Doyle,Structural Genomics Consortium (Sgc)

Key ref:

M.Soundararajan et al. (2008). 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. PubMed id: 18434541 DOI: 10.1073/pnas.0801508105

Date:

22-Dec-06 Release date: 06-Feb-07

Protein chains

P08754  (GNAI3_HUMAN) -  Guanine nucleotide-binding protein G(i) subunit alpha-3 from Homo sapiens

Seq: 354 a.a.

Struc: 316 a.a.

Protein chain

P57771  (RGS8_HUMAN) -  Regulator of G-protein signaling 8 from Homo sapiens

Seq: 180 a.a.

Struc: 131 a.a.

Protein chain

P57771  (RGS8_HUMAN) -  Regulator of G-protein signaling 8 from Homo sapiens

Seq: 180 a.a.

Struc: 116 a.a.

DOI no: 10.1073/pnas.0801508105

Proc Natl Acad Sci U S A 105:6457-6462 (2008)

PubMed id: 18434541

Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits.

M.Soundararajan, F.S.Willard, A.J.Kimple, A.P.Turnbull, L.J.Ball, G.A.Schoch, C.Gileadi, O.Y.Fedorov, E.F.Dowler, V.A.Higman, S.Q.Hutsell, M.Sundström, D.A.Doyle, D.P.Siderovski.

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.

Selected figure(s)

Figure 1.
Heterogeneity in the αV–αVII regions of R12 subfamily RGS domains versus the canonical RGS domain fold of R4, R7, and RZ subfamily members. (A) Apo-RGS domains of R4 subfamily member RGS8 (green; PDB ID 2IHD), R7 subfamily member RGS9 (orange; PDB ID 1FQI), and RZ subfamily member RGS19 (gray; PDB ID 1CMZ) were aligned along helices αIV and αV and superimposed by using PyMOL. (B–D) Apo-RGS domains of RGS14 (B) (blue; PDB ID 2JNU), RGS10 from this study (C) (salmon; PDB ID 2I59), and RGS10 from Yokoyama et al. (D) (light purple; PDB ID 2DLR) are presented to highlight differences in the αV–αVI–αVII region. The heterogeneous αVI regions are specifically highlighted in cyan (B), red (C), and magenta (D), respectively.

Figure 2.
Predicted structural determinants of Gα selectivity by RGS2. (A) RGS1 (gray-blue) bound to Gα[i1] (α1 helix in light red; switch I in orange) is presented to highlight the Gα switch-I interaction interface (PDB ID 2GTP). Asp-172 of RGS1 is within hydrogen-bonding distance of the backbone amine of Thr-182 in Gα[i1] and additionally stabilized by the terminal amines of the highly conserved Arg-176 in the RGS1 αVII helix. Ser-95 is placed within close proximity (≤4.0 Å) of three Gα[i1] residues (Thr-182, Gly-183, and Lys-210). (B) Residues 170–190 of RGS2 (PDB ID 2AF0) were superimposed on residues 159–179 of RGS1 from the RGS1/Gα[i1] complex (PDB ID 2GTP) with an r.m.s.d. of 0.5 Å. RGS1 is not shown, RGS2 is presented in green, and Gα[i1] is rendered in light red (α1 helix) and orange (switch I). Asparagine at position 184 in RGS2 (normally an aspartate in R4 subfamily members) does not allow for the hydrogen bond to the peptide bond amine of Thr-182 in Gα[i1]; however, Asn-184 can potentially form a hydrogen bond with the backbone carbonyl of Lys-180. The increased atomic radius of Cys-106 in RGS2 (versus serine in RGS1) may cause steric hindrance with the switch-I backbone and the side-chain of Lys-210.

Figures were selected by an automated process.