3MS9

ABL kinase in complex with imatinib and a fragment (FRAG1) in the myristate pocket

Summary for 3MS9

• Entry DOI: 10.2210/pdb3ms9/pdb
• Related: 3MSS
• Descriptor: Tyrosine-protein kinase ABL1, 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE, methyl 2-amino-4-chlorobenzoate, ... (5 entities in total)
• Functional Keywords: kinase, fragment-based screening, fbs, transferase, transferase-transferase regulator complex, transferase/transferase regulator
• Biological source: Mus musculus (mouse)
• Cellular location: Cytoplasm, cytoskeleton: P00520
• Total number of polymer chains: 2
• Total formula weight: 69058.19

Authors

Cowan-Jacob, S.W.,Rummel, G.,Fendrich, G. (deposition date: 2010-04-29, release date: 2010-05-26, Last modification date: 2024-02-21)

Primary citation

Jahnke, W.,Grotzfeld, R.M.,Pelle, X.,Strauss, A.,Fendrich, G.,Cowan-Jacob, S.W.,Cotesta, S.,Fabbro, D.,Furet, P.,Mestan, J.,Marzinzik, A.L.
Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay.
J.Am.Chem.Soc., 132:7043-7048, 2010

PubMed Abstract: Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for the treatment of CML. Using fragment-based screening, a search for novel Abl inhibitors that bind to the myristate pocket was carried out. Here we show that not all myristate ligands are functional inhibitors, but that the conformational state of C-terminal helix_I is a structural determinant for functional activity. We present an NMR-based conformational assay to monitor the conformation of this crucial helix_I and show that myristate ligands that bend helix_I are functional antagonists, whereas ligands that bind to the myristate pocket but do not induce this conformational change are kinase agonists. Activation of c-Abl by allosteric agonists has been confirmed in a biochemical assay.

PubMed: 20450175
DOI: 10.1021/ja101837n

Experimental method

X-RAY DIFFRACTION (1.8 Å)