3G5D

Kinase domain of cSrc in complex with Dasatinib

Summary for 3G5D

• Entry DOI: 10.2210/pdb3g5d/pdb
• Related: 3F3T 3F3U 3F3V 3F3W
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: type ii, dfg-out, tyrosine-protein kinase, dasatinib, atp-binding, kinase, lipoprotein, myristate, nucleotide-binding, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, transferase
• Biological source: Gallus gallus (chicken)
• Cellular location: Cell membrane (By similarity): P00523
• Total number of polymer chains: 2
• Total formula weight: 66645.62

Authors

Grutter, C.,Kluter, S.,Rauh, D. (deposition date: 2009-02-05, release date: 2009-06-02, Last modification date: 2023-11-01)

Primary citation

Getlik, M.,Grutter, C.,Simard, J.R.,Kluter, S.,Rabiller, M.,Rode, H.B.,Robubi, A.,Rauh, D.
Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc
J.Med.Chem., 52:3915-3926, 2009

PubMed 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.

PubMed: 19462975
DOI: 10.1021/jm9002928

Experimental method

X-RAY DIFFRACTION (2.2 Å)