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PDBsum entry 1aa9

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protein ligands metals links
Proto-oncogene PDB id
1aa9
Jmol
Contents
Protein chain
171 a.a. *
Ligands
GDP
Metals
_MG
* Residue conservation analysis
PDB id:
1aa9
Name: Proto-oncogene
Title: Human c-ha-ras(1-171)(dot)gdp, nmr, minimized average structure
Structure: C-ha-ras. Chain: a. Fragment: residues 1 - 171. Engineered: yes. Other_details: complexed to guanosine 5'-diphosphate
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: human c-ha-ras gene. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 1 models
Authors: Y.Ito,Y.Yamasaki,Y.Muto,G.Kawai,S.Nishimura,T.Miyazawa, S.Yokoyama,Riken Structural Genomics/proteomics Initiative (Rsgi)
Key ref: Y.Ito et al. (1997). Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein. Biochemistry, 36, 9109-9119. PubMed id: 9230043 DOI: 10.1021/bi970296u
Date:
27-Jan-97     Release date:   29-Jul-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01112  (RASH_HUMAN) -  GTPase HRas
Seq:
Struc:
189 a.a.
171 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   9 terms 
  Biological process     Fc-epsilon receptor signaling pathway   56 terms 
  Biochemical function     nucleotide binding     4 terms  

 

 
DOI no: 10.1021/bi970296u Biochemistry 36:9109-9119 (1997)
PubMed id: 9230043  
 
 
Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein.
Y.Ito, K.Yamasaki, J.Iwahara, T.Terada, A.Kamiya, M.Shirouzu, Y.Muto, G.Kawai, S.Yokoyama, E.D.Laue, M.Wälchli, T.Shibata, S.Nishimura, T.Miyazawa.
 
  ABSTRACT  
 
The backbone 1H, 13C, and 15N resonances of the c-Ha-Ras protein [a truncated version consisting of residues 1-171, Ras(1-171)] bound with GMPPNP (a slowly hydrolyzable analogue of GTP) were assigned and compared with those of the GDP-bound Ras(1-171). The backbone amide resonances of amino acid residues 10-13, 21, 31-39, 57-64, and 71 of Ras(1-171).GMPPNP, but not those of Ras(1-171).GDP, were extremely broadened, whereas other residues of Ras(1-171).GMPPNP exhibited amide resonances nearly as sharp as those of Ras(1-171). GDP. The residues exhibiting the extreme broadening, except for residues 21 and 71, are localized in three functional loop regions [loops L1, L2 (switch I), and L4 (switch II)], which are involved in hydrolysis of GTP and interactions with other proteins. From the temperature and magnetic field strength dependencies of the backbone amide resonance intensities, the extreme broadening was ascribed to the exchange at an intermediate rate on the NMR time scale. It was shown that the Ras(1-171) protein bound with GTP or GTPgammaS (another slowly hydrolyzable analogue of GTP) exhibits the same type of broadening. Therefore, it is a characteristic feature of the GTP-bound form of Ras that the L1, L2, and L4 loop regions, but not other regions, are in a rather slow interconversion between two or more stable conformers. This phenomenon, termed a "regional polysterism", of these loop regions may be related with their multifunctionality: the GTP-dependent interactions with several downstream target groups such as the Raf and RalGDS families and also with the GTPase activating protein (GAP) family. In fact, the binding of Ras(1-171).GMPPNP with the Ras-binding domain (residues 51-131) of c-Raf-1 was shown to eliminate the regional polysterism nearly completely. It was indicated, therefore, that each target/regulator selects its appropriate conformer among those presented by the "polysteric" binding interface of Ras. As the downstream target groups exhibit no apparent sequence homology to each other, it is possible that one target group prefers a conformer different from that preferred by another group. The involvement of loop L1 in the regional polysterism might suggest that the negative regulators, GAPs, bind to the polysteric binding interface (loops L2 and L4) of Ras and cooperatively select a conformer suitable for transition of the GTPase catalytic center, involving loops L1 and L4, into the highly active state.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
23178454 R.Baker, S.M.Lewis, A.T.Sasaki, E.M.Wilkerson, J.W.Locasale, L.C.Cantley, B.Kuhlman, H.G.Dohlman, and S.L.Campbell (2013).
Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function.
  Nat Struct Mol Biol, 20, 46-52.  
20649471 J.Heo (2011).
Redox control of GTPases: from molecular mechanisms to functional significance in health and disease.
  Antioxid Redox Signal, 14, 689-724.  
21456702 K.Itoh, and M.Sasai (2011).
Statistical mechanics of protein allostery: roles of backbone and side-chain structural fluctuations.
  J Chem Phys, 134, 125102.  
20949621 L.Gremer, T.Merbitz-Zahradnik, R.Dvorsky, I.C.Cirstea, C.P.Kratz, M.Zenker, A.Wittinghofer, and M.R.Ahmadian (2011).
Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.
  Hum Mutat, 32, 33-43.  
20973973 B.U.Klink, and A.J.Scheidig (2010).
New insight into the dynamic properties and the active site architecture of H-Ras p21 revealed by X-ray crystallography at very high resolution.
  BMC Struct Biol, 10, 38.  
20018869 G.M.Gasmi-Seabrook, C.B.Marshall, M.Cheung, B.Kim, F.Wang, Y.J.Jang, T.W.Mak, V.Stambolic, and M.Ikura (2010).
Real-time NMR study of guanine nucleotide exchange and activation of RhoA by PDZ-RhoGEF.
  J Biol Chem, 285, 5137-5145.  
20131908 N.Nassar, K.Singh, and M.Garcia-Diaz (2010).
Structure of the dominant negative S17N mutant of Ras.
  Biochemistry, 49, 1970-1974.
PDB code: 3lo5
20685651 S.Karassek, C.Berghaus, M.Schwarten, C.G.Goemans, N.Ohse, G.Kock, K.Jockers, S.Neumann, S.Gottfried, C.Herrmann, R.Heumann, and R.Stoll (2010).
Ras homolog enriched in brain (Rheb) enhances apoptotic signaling.
  J Biol Chem, 285, 33979-33991.
PDB code: 2l0x
19651783 M.M.Edreira, S.Li, D.Hochbaum, S.Wong, A.A.Gorfe, F.Ribeiro-Neto, V.L.Woods, and D.L.Altschuler (2009).
Phosphorylation-induced conformational changes in Rap1b: allosteric effects on switch domains and effector loop.
  J Biol Chem, 284, 27480-27486.  
18713003 L.Gremer, B.Gilsbach, M.R.Ahmadian, and A.Wittinghofer (2008).
Fluoride complexes of oncogenic Ras mutants to study the Ras-RasGap interaction.
  Biol Chem, 389, 1163-1171.  
18219391 M.M.Harraz, J.J.Marden, W.Zhou, Y.Zhang, A.Williams, V.S.Sharov, K.Nelson, M.Luo, H.Paulson, C.Schöneich, and J.F.Engelhardt (2008).
SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model.
  J Clin Invest, 118, 659-670.  
18006505 R.Modha, L.J.Campbell, D.Nietlispach, H.R.Buhecha, D.Owen, and H.R.Mott (2008).
The Rac1 polybasic region is required for interaction with its effector PRK1.
  J Biol Chem, 283, 1492-1500.
PDB code: 2rmk
18073111 G.Buhrman, G.Wink, and C.Mattos (2007).
Transformation efficiency of RasQ61 mutants linked to structural features of the switch regions in the presence of Raf.
  Structure, 15, 1618-1629.
PDB codes: 2rga 2rgb 2rgc 2rgd 2rge 2rgg
17302736 M.Spoerner, A.Nuehs, C.Herrmann, G.Steiner, and H.R.Kalbitzer (2007).
Slow conformational dynamics of the guanine nucleotide-binding protein Ras complexed with the GTP analogue GTPgammaS.
  FEBS J, 274, 1419-1433.  
16415860 J.Kozuka, H.Yokota, Y.Arai, Y.Ishii, and T.Yanagida (2006).
Dynamic polymorphism of single actin molecules in the actin filament.
  Nat Chem Biol, 2, 83-86.  
16791740 K.Kurashima-Ito, T.Ikeya, H.Senbongi, H.Tochio, T.Mikawa, T.Shibata, and Y.Ito (2006).
Heteronuclear multidimensional NMR and homology modelling studies of the C-terminal nucleotide-binding domain of the human mitochondrial ABC transporter ABCB6.
  J Biomol NMR, 35, 53-71.  
17053066 N.Van Eps, W.M.Oldham, H.E.Hamm, and W.L.Hubbell (2006).
Structural and dynamical changes in an alpha-subunit of a heterotrimeric G protein along the activation pathway.
  Proc Natl Acad Sci U S A, 103, 16194-16199.  
16571678 S.Barale, D.McCusker, and R.A.Arkowitz (2006).
Cdc42p GDP/GTP cycling is necessary for efficient cell fusion during yeast mating.
  Mol Biol Cell, 17, 2824-2838.  
16080156 A.Schlessinger, and B.Rost (2005).
Protein flexibility and rigidity predicted from sequence.
  Proteins, 61, 115-126.  
15684418 J.Heo, and S.L.Campbell (2005).
Superoxide anion radical modulates the activity of Ras and Ras-related GTPases by a radical-based mechanism similar to that of nitric oxide.
  J Biol Chem, 280, 12438-12445.  
16235217 M.Spoerner, T.F.Prisner, M.Bennati, M.M.Hertel, N.Weiden, T.Schweins, and H.R.Kalbitzer (2005).
Conformational states of human H-Ras detected by high-field EPR, ENDOR, and 31P NMR spectroscopy.
  Magn Reson Chem, 43, S74-S83.  
15653425 E.J.Helmreich (2004).
Structural flexibility of small GTPases. Can it explain their functional versatility?
  Biol Chem, 385, 1121-1136.  
12581669 C.Herrmann (2003).
Ras-effector interactions: after one decade.
  Curr Opin Struct Biol, 13, 122-129.  
12842038 G.Buhrman, V.de Serrano, and C.Mattos (2003).
Organic solvents order the dynamic switch II in Ras crystals.
  Structure, 11, 747-751.
PDB codes: 1p2s 1p2t 1p2u 1p2v
14556626 M.Geyer, C.Wilde, J.Selzer, K.Aktories, and H.R.Kalbitzer (2003).
Glucosylation of Ras by Clostridium sordellii lethal toxin: consequences for effector loop conformations observed by NMR spectroscopy.
  Biochemistry, 42, 11951-11959.  
12717016 S.Kuppens, M.Hellings, J.Jordens, S.Verheyden, and Y.Engelborghs (2003).
Conformational states of the switch I region of Ha-ras-p21 in hinge residue mutants studied by fluorescence lifetime and fluorescence anisotropy measurements.
  Protein Sci, 12, 930-938.  
12084068 M.Stumber, C.Herrmann, S.Wohlgemuth, H.R.Kalbitzer, W.Jahn, and M.Geyer (2002).
Synthesis, characterization and application of two nucleoside triphosphate analogues, GTPgammaNH(2) and GTPgammaF.
  Eur J Biochem, 269, 3270-3278.  
11701921 I.R.Vetter, and A.Wittinghofer (2001).
The guanine nucleotide-binding switch in three dimensions.
  Science, 294, 1299-1304.  
11246021 M.Kosloff, and Z.Selinger (2001).
Substrate assisted catalysis -- application to G proteins.
  Trends Biochem Sci, 26, 161-166.  
11320243 M.Spoerner, C.Herrmann, I.R.Vetter, H.R.Kalbitzer, and A.Wittinghofer (2001).
Dynamic properties of the Ras switch I region and its importance for binding to effectors.
  Proc Natl Acad Sci U S A, 98, 4944-4949.
PDB code: 1iaq
11188692 C.T.Farrar, J.Ma, D.J.Singel, and C.J.Halkides (2000).
Structural changes induced in p21Ras upon GAP-334 complexation as probed by ESEEM spectroscopy and molecular-dynamics simulation.
  Structure, 8, 1279-1287.  
11112548 M.Fridman, F.Walker, B.Catimel, T.Domagala, E.Nice, and A.Burgess (2000).
c-Raf-1 RBD associates with a subset of active v-H-Ras.
  Biochemistry, 39, 15603-15611.  
10692340 T.Wazawa, Y.Ishii, T.Funatsu, and T.Yanagida (2000).
Spectral fluctuation of a single fluorophore conjugated to a protein molecule.
  Biophys J, 78, 1561-1569.  
10744353 Y.Ishii, Y.Kimura, K.Kitamura, H.Tanaka, T.Wazawa, and T.Yanagida (2000).
Imaging and nano-manipulation of single actomyosin motors at work.
  Clin Exp Pharmacol Physiol, 27, 229-237.  
10574788 A.J.Scheidig, C.Burmester, and R.S.Goody (1999).
The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins.
  Structure, 7, 1311-1324.
PDB codes: 1ctq 1qra
9434896 M.Geyer, and A.Wittinghofer (1997).
GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins.
  Curr Opin Struct Biol, 7, 786-792.  
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.