PDBsum entry 3t04

Signaling protein/protein binding

PDB id: 3t04

Contents

Protein chains

98 a.a.

103 a.a.

Ligands

GOL ×4

SO4

Waters ×127

PDB id:

3t04

Name:

Signaling protein/protein binding

Title:

Crystal structure of monobody 7c12/abl1 sh2 domain complex

Structure:

Tyrosine-protein kinase abl1. Chain: a. Fragment: sh2 domain (unp residues 112-232). Synonym: abelson murine leukemia viral oncogene homolog 1, proto- oncogenE C-abl, p150. Engineered: yes. Monobody 7c12. Chain: d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: abl, abl1, jtk7. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.193 R-free: 0.251

Authors:

J.B.Wojcik,A.M.Wyrzucki,S.Koide

Key ref:

F.Grebien et al. (2011). Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Cell, 147, 306-319. PubMed id: 22000011

Date:

19-Jul-11 Release date: 23-Nov-11

Protein chain

P00519  (ABL1_HUMAN) -  Tyrosine-protein kinase ABL1 from Homo sapiens

Seq: 1130 a.a.

Struc: 98 a.a.

Protein chain

No UniProt id for this chain

Struc: 103 a.a.

Enzyme reactions

• Enzyme class: Chain A: 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

Cell 147:306-319 (2011)

PubMed id: 22000011

Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis.

F.Grebien, O.Hantschel, J.Wojcik, I.Kaupe, B.Kovacic, A.M.Wyrzucki, G.D.Gish, S.Cerny-Reiterer, A.Koide, H.Beug, T.Pawson, P.Valent, S.Koide, G.Superti-Furga.

ABSTRACT

Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of Bcr-Abl in addition to the kinase active site are strongly desirable. Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. Disruption of this interface led to inhibition of downstream events critical for CML signaling and, importantly, completely abolished leukemia formation in mice. Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. This work validates the SH2-kinase interface as an allosteric target for therapeutic intervention.