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PDBsum entry 3lbn

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protein ligands metals links
Oncoprotein PDB id
3lbn
Jmol
Contents
Protein chain
166 a.a. *
Ligands
GNP
Metals
_MG ×3
_CA
Waters ×110
* Residue conservation analysis
PDB id:
3lbn
Name: Oncoprotein
Title: Ras soaked in magnesium acetate
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.
Resolution:
1.86Å     R-factor:   0.187     R-free:   0.224
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
Date:
08-Jan-10     Release date:   02-Mar-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01112  (RASH_HUMAN) -  GTPase HRas
Seq:
Struc:
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.
 
  ABSTRACT  
 
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.  
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.