5DC0

CRYSTAL STRUCTURE OF MONOBODY GG3/ABL1 SH2 DOMAIN COMPLEX

Summary for 5DC0

• Entry DOI: 10.2210/pdb5dc0/pdb
• Related: 5DC4 5DC9
• Descriptor: Fibronectin, Tyrosine-protein kinase ABL1 (3 entities in total)
• Functional Keywords: engineered binding protein, antibody mimic, protein-protein complex, sh2 domain, tyrosine-protein kinase, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 23437.98

Authors

Wojcik, J.B.,Grabe, G.,Koide, S. (deposition date: 2015-08-22, release date: 2016-03-02, Last modification date: 2024-03-06)

Primary citation

Wojcik, J.,Lamontanara, A.J.,Grabe, G.,Koide, A.,Akin, L.,Gerig, B.,Hantschel, O.,Koide, S.
Allosteric Inhibition of Bcr-Abl Kinase by High Affinity Monobody Inhibitors Directed to the Src Homology 2 (SH2)-Kinase Interface.
J.Biol.Chem., 291:8836-8847, 2016

PubMed Abstract: Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase domains and to the phosphotyrosine-binding site of the SH2 domain, respectively, inhibits the Bcr-Abl kinase activity. Because the latter monobody inhibits processive phosphorylation by Bcr-Abl and the SH2-kinase interface is occluded in the active kinase, it remained undetermined whether targeting the SH2-kinase interface alone was sufficient for Bcr-Abl inhibition. To address this question, we generated new, higher affinity monobodies with single nanomolar KD values targeting the kinase-binding surface of SH2. Structural and mutagenesis studies revealed the molecular underpinnings of the monobody-SH2 interactions. Importantly, the new monobodies inhibited Bcr-Abl kinase activity in vitro and in cells, and they potently induced cell death in chronic myelogenous leukemia cell lines. This work provides strong evidence for the SH2-kinase interface as a pharmacologically tractable site for allosteric inhibition of Bcr-Abl.

PubMed: 26912659
DOI: 10.1074/jbc.M115.707901

Experimental method

X-RAY DIFFRACTION (2.23 Å)