PDBsum entry 3g6g

Transferase

PDB id: 3g6g

Contents

Protein chains

264 a.a. *

Ligands

G6G ×2

GOL ×2

Waters ×58

* Residue conservation analysis

PDB id:

3g6g

Name:

Transferase

Title:

Equally potent inhibition of c-src and abl by compounds that recognize inactive kinase conformations

Structure:

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

Source:

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

Resolution:

2.31Å R-factor: 0.231 R-free: 0.277

Authors:

M.A.Seeliger,P.Ranjitkar,C.Kasap,Y.Shan,D.E.Shaw,N.P.Shah,J.Kuriyan, D.J.Maly

Key ref:

M.A.Seeliger et al. (2009). Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations. Cancer Res, 69, 2384-2392. PubMed id: 19276351 DOI: 10.1158/0008-5472.CAN-08-3953

Date:

06-Feb-09 Release date: 24-Mar-09

Protein chains

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

Seq: 533 a.a.

Struc: 264 a.a.

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

DOI no: 10.1158/0008-5472.CAN-08-3953

Cancer Res 69:2384-2392 (2009)

PubMed id: 19276351

Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations.

M.A.Seeliger, P.Ranjitkar, C.Kasap, Y.Shan, D.E.Shaw, N.P.Shah, J.Kuriyan, D.J.Maly.

ABSTRACT

Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile "gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells.