3T04

Crystal structure of monobody 7c12/abl1 sh2 domain complex

Summary for 3T04

• Entry DOI: 10.2210/pdb3t04/pdb
• Descriptor: Tyrosine-protein kinase ABL1, MONOBODY 7C12, GLYCEROL, ... (5 entities in total)
• Functional Keywords: engineered binding protein, antibody mimic, protein-protein complex, sh2 domain, atp-binding, phosphoprotein, tyrosine-protein kinase, signaling protein-protein binding complex, signaling protein/protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• Total number of polymer chains: 2
• Total formula weight: 25465.86

Authors

Wojcik, J.B.,Wyrzucki, A.M.,Koide, S. (deposition date: 2011-07-19, release date: 2011-11-23, Last modification date: 2023-09-13)

Primary citation

Grebien, F.,Hantschel, O.,Wojcik, J.,Kaupe, I.,Kovacic, B.,Wyrzucki, A.M.,Gish, G.D.,Cerny-Reiterer, S.,Koide, A.,Beug, H.,Pawson, T.,Valent, P.,Koide, S.,Superti-Furga, G.
Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis.
Cell(Cambridge,Mass.), 147:306-319, 2011

PubMed 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.

PubMed: 22000011
DOI: 10.1016/j.cell.2011.08.046

Experimental method

X-RAY DIFFRACTION (2.1 Å)