PDBsum entry 3k8y

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Oncoprotein PDB id
Protein chain
166 a.a. *
_CA ×2
_MG ×2
Waters ×184
* Residue conservation analysis
PDB id:
Name: Oncoprotein
Title: Allosteric modulation of h-ras gtpase
Structure: Gtpase hras. Chain: a. Fragment: unp residues 1-166. Synonym: transforming protein p21, p21ras, h-ras-1, c-h-ras gtpase hras, n-terminally processed. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hras, hras1. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.30Å     R-factor:   0.201     R-free:   0.227
Authors: G.Holzapfel,G.Buhrman,C.Mattos
Key ref: G.Buhrman et al. (2010). Allosteric modulation of Ras positions Q61 for a direct role in catalysis. Proc Natl Acad Sci U S A, 107, 4931-4936. PubMed id: 20194776
15-Oct-09     Release date:   02-Mar-10    
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Protein chain
Pfam   ArchSchema ?
P01112  (RASH_HUMAN) -  GTPase HRas
189 a.a.
166 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   2 terms 
  Biological process     signal transduction   4 terms 
  Biochemical function     GTP binding     1 term  


Proc Natl Acad Sci U S A 107:4931-4936 (2010)
PubMed id: 20194776  
Allosteric modulation of Ras positions Q61 for a direct role in catalysis.
G.Buhrman, G.Holzapfel, S.Fetics, C.Mattos.
Ras and its effector Raf are key mediators of the Ras/Raf/MEK/ERK signal transduction pathway. Mutants of residue Q61 impair the GTPase activity of Ras and are found prominently in human cancers. Yet the mechanism through which Q61 contributes to catalysis has been elusive. It is thought to position the catalytic water molecule for nucleophilic attack on the gamma-phosphate of GTP. However, we previously solved the structure of Ras from crystals with symmetry of the space group R32 in which switch II is disordered and found that the catalytic water molecule is present. Here we present a structure of wild-type Ras with calcium acetate from the crystallization mother liquor bound at a site remote from the active site and likely near the membrane. This results in a shift in helix 3/loop 7 and a network of H-bonding interactions that propagates across the molecule, culminating in the ordering of switch II and placement of Q61 in the active site in a previously unobserved conformation. This structure suggests a direct catalytic role for Q61 where it interacts with a water molecule that bridges one of the gamma-phosphate oxygen atoms to the hydroxyl group of Y32 to stabilize the transition state of the hydrolysis reaction. We propose that Raf together with the binding of Ca(2+) and a negatively charged group mimicked in our structure by the acetate molecule induces the ordering of switch I and switch II to complete the active site of Ras.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21993244 Y.Pylayeva-Gupta, E.Grabocka, and D.Bar-Sagi (2011).
RAS oncogenes: weaving a tumorigenic web.
  Nat Rev Cancer, 11, 761-774.  
20520657 R.Huang, I.Martinez-Ferrando, and P.A.Cole (2010).
Enhanced interrogation: emerging strategies for cell signaling inhibition.
  Nat Struct Mol Biol, 17, 646-649.  
  20838576 S.Lukman, B.J.Grant, A.A.Gorfe, G.H.Grant, and J.A.McCammon (2010).
The distinct conformational dynamics of K-Ras and H-Ras A59G.
  PLoS Comput Biol, 6, 0.  
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