Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.

Cell | Jun 16, 2006

http://www.ncbi.nlm.nih.gov/pubmed/16777603

The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation. This suggests that the kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Using further mutational analysis and crystallography we demonstrate that the autoinhibited conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed by two kinase domains thus explains the activation of EGFR-family receptors by homo- or heterodimerization.

Pubmed ID: 16777603 RIS Download

Mesh terms: Allosteric Regulation | Amino Acid Sequence | Animals | Crystallography, X-Ray | Cyclin-Dependent Kinases | Dimerization | Enzyme Activation | Humans | Leucine | Mice | Models, Molecular | Molecular Sequence Data | Mutation | NIH 3T3 Cells | Phosphorylation | Protein Conformation | Protein Structure, Tertiary | Receptor, Epidermal Growth Factor | src-Family Kinases

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA74305
  • Agency: NCI NIH HHS, Id: R01 CA96504

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.