PDBsum entry 3f3v

Transferase

PDB id: 3f3v

Contents

Protein chains

261 a.a. *

Ligands

1BU ×2

Waters ×53

* Residue conservation analysis

PDB id:

3f3v

Name:

Transferase

Title:

Kinase domain of csrc in complex with inhibitor rl45 (type ii)

Structure:

Proto-oncogene tyrosine-protein kinase src. Chain: a, b. Fragment: kinase domain, unp residues 251-533. Synonym: pp60c-src, p60-src, c-src. Engineered: yes. Mutation: yes

Source:

Gallus gallus. Chicken. Organism_taxid: 9031. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.60Å R-factor: 0.213 R-free: 0.284

Authors:

C.Grutter,S.Kluter,M.Getlik,D.Rauh

Key ref:

M.Getlik et al. (2009). Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc. J Med Chem, 52, 3915-3926. PubMed id: 19462975

Date:

31-Oct-08 Release date: 02-Jun-09

Protein chains

P00523  (SRC_CHICK) -  Proto-oncogene tyrosine-protein kinase Src from Gallus gallus

Seq: 533 a.a.

Struc: 261 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

J Med Chem 52:3915-3926 (2009)

PubMed id: 19462975

Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc.

M.Getlik, C.Grütter, J.R.Simard, S.Klüter, M.Rabiller, H.B.Rode, A.Robubi, D.Rauh.

ABSTRACT

The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.