PDBsum entry 2ihd

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Signaling protein PDB id
Jmol PyMol
Protein chain
127 a.a. *
Waters ×170
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Crystal structure of human regulator of g-protein signaling
Structure: Regulator of g-protein signaling 8. Chain: a. Synonym: rgs8. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: rgs8. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.70Å     R-factor:   0.177     R-free:   0.211
Authors: A.P.Turnbull,E.Papagrigoriou,E.Ugochukwu,E.Salah,C.Gileadi,N C.Bhatia,O.Gileadi,J.Bray,J.Elkins,F.Von Delft,J.Weigelt,A. C.Arrowsmith,M.Sundstrom,D.A.Doyle,Structural Genomics Cons (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
26-Sep-06     Release date:   21-Nov-06    
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Protein chain
Pfam   ArchSchema ?
P57771  (RGS8_HUMAN) -  Regulator of G-protein signaling 8
180 a.a.
127 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain


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.
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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21685921 M.Kosloff, A.M.Travis, D.E.Bosch, D.P.Siderovski, and V.Y.Arshavsky (2011).
Integrating energy calculations with functional assays to decipher the specificity of G protein-RGS protein interactions.
  Nat Struct Mol Biol, 18, 846-853.  
21036862 Q.Xu, and R.L.Dunbrack (2011).
The protein common interface database (ProtCID)--a comprehensive database of interactions of homologous proteins in multiple crystal forms.
  Nucleic Acids Res, 39, D761-D770.  
21210729 R.Day, X.Qu, R.Swanson, Z.Bohannan, R.Bliss, and J.Tsai (2011).
Relative packing groups in template-based structure prediction: cooperative effects of true positive constraints.
  J Comput Biol, 18, 17-26.  
20217615 A.J.Kimple, R.E.Muller, D.P.Siderovski, and F.S.Willard (2010).
A capture coupling method for the covalent immobilization of hexahistidine tagged proteins for surface plasmon resonance.
  Methods Mol Biol, 627, 91.  
20002516 J.N.Talbot, D.L.Roman, M.J.Clark, R.A.Roof, J.J.Tesmer, R.R.Neubig, and J.R.Traynor (2010).
Differential modulation of mu-opioid receptor signaling to adenylyl cyclase by regulators of G protein signaling proteins 4 or 8 and 7 in permeabilised C6 cells is Galpha subtype dependent.
  J Neurochem, 112, 1026-1034.  
20201861 J.Traynor (2010).
Regulator of G protein-signaling proteins and addictive drugs.
  Ann N Y Acad Sci, 1187, 341-352.  
20351284 N.A.Lambert, C.A.Johnston, S.D.Cappell, S.Kuravi, A.J.Kimple, F.S.Willard, and D.P.Siderovski (2010).
Regulators of G-protein signaling accelerate GPCR signaling kinetics and govern sensitivity solely by accelerating GTPase activity.
  Proc Natl Acad Sci U S A, 107, 7066-7071.  
20859254 P.Maurice, A.M.Daulat, R.Turecek, K.Ivankova-Susankova, F.Zamponi, M.Kamal, N.Clement, J.L.Guillaume, B.Bettler, C.Galès, P.Delagrange, and R.Jockers (2010).
Molecular organization and dynamics of the melatonin MT₁ receptor/RGS20/G(i) protein complex reveal asymmetry of receptor dimers for RGS and G(i) coupling.
  EMBO J, 29, 3646-3659.  
20017116 R.L.Rich, and D.G.Myszka (2010).
Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'.
  J Mol Recognit, 23, 1.  
20217614 S.Q.Hutsell, R.J.Kimple, D.P.Siderovski, F.S.Willard, and A.J.Kimple (2010).
High-affinity immobilization of proteins using biotin- and GST-based coupling strategies.
  Methods Mol Biol, 627, 75-90.  
19489729 A.Edwards (2009).
Large-scale structural biology of the human proteome.
  Annu Rev Biochem, 78, 541-568.  
19478087 A.J.Kimple, M.Soundararajan, S.Q.Hutsell, A.K.Roos, D.J.Urban, V.Setola, B.R.Temple, B.L.Roth, S.Knapp, F.S.Willard, and D.P.Siderovski (2009).
Structural determinants of G-protein alpha subunit selectivity by regulator of G-protein signaling 2 (RGS2).
  J Biol Chem, 284, 19402-19411.
PDB code: 2v4z
19736320 C.H.Nguyen, H.Ming, P.Zhao, L.Hugendubler, R.Gros, S.R.Kimball, and P.Chidiac (2009).
Translational control by RGS2.
  J Cell Biol, 186, 755-765.  
19319189 F.S.Willard, M.D.Willard, A.J.Kimple, M.Soundararajan, E.A.Oestreich, X.Li, N.A.Sowa, R.J.Kimple, D.A.Doyle, C.J.Der, M.J.Zylka, W.D.Snider, and D.P.Siderovski (2009).
Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector.
  PLoS ONE, 4, e4884.  
19521673 G.R.Anderson, E.Posokhova, and K.A.Martemyanov (2009).
The R7 RGS protein family: multi-subunit regulators of neuronal G protein signaling.
  Cell Biochem Biophys, 54, 33-46.  
19820068 T.Zielinski, A.J.Kimple, S.Q.Hutsell, M.D.Koeff, D.P.Siderovski, and R.G.Lowery (2009).
Two Galpha(i1) rate-modifying mutations act in concert to allow receptor-independent, steady-state measurements of RGS protein activity.
  J Biomol Screen, 14, 1195-1206.  
19164534 Y.Oka, L.R.Saraiva, Y.Y.Kwan, and S.I.Korsching (2009).
The fifth class of Galpha proteins.
  Proc Natl Acad Sci U S A, 106, 1484-1489.  
  19641738 Y.Oka, and S.I.Korsching (2009).
The fifth element in animal Galpha protein evolution.
  Commun Integr Biol, 2, 227-229.  
18936096 A.Shankaranarayanan, D.M.Thal, V.M.Tesmer, D.L.Roman, R.R.Neubig, T.Kozasa, and J.J.Tesmer (2008).
Assembly of high order G alpha q-effector complexes with RGS proteins.
  J Biol Chem, 283, 34923-34934.  
18984596 F.S.Willard, Z.Zheng, J.Guo, G.J.Digby, A.J.Kimple, J.M.Conley, C.A.Johnston, D.Bosch, M.D.Willard, V.J.Watts, N.A.Lambert, S.R.Ikeda, Q.Du, and D.P.Siderovski (2008).
A point mutation to Galphai selectively blocks GoLoco motif binding: direct evidence for Galpha.GoLoco complexes in mitotic spindle dynamics.
  J Biol Chem, 283, 36698-36710.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.