3G0F

KIT kinase domain mutant D816H in complex with sunitinib

Summary for 3G0F

• Entry DOI: 10.2210/pdb3g0f/pdb
• Related: 3G0E
• Descriptor: Mast/stem cell growth factor receptor, N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbo xamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kit kinase domain, sutent binding, drug resistance, atp-binding, disease mutation, glycoprotein, immunoglobulin domain, kinase, membrane, nucleotide-binding, phosphoprotein, polymorphism, proto-oncogene, receptor, transmembrane, tyrosine-protein kinase, transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cell membrane; Single-pass type I membrane protein. Isoform 3: Cytoplasm: P10721
• Total number of polymer chains: 2
• Total formula weight: 77373.49

Authors

Gajiwala, K.S.,Wu, J.C.,Lunney, E.A.,Demetri, G.D. (deposition date: 2009-01-27, release date: 2009-02-24, Last modification date: 2024-04-03)

Primary citation

Gajiwala, K.S.,Wu, J.C.,Christensen, J.,Deshmukh, G.D.,Diehl, W.,DiNitto, J.P.,English, J.M.,Greig, M.J.,He, Y.A.,Jacques, S.L.,Lunney, E.A.,McTigue, M.,Molina, D.,Quenzer, T.,Wells, P.A.,Yu, X.,Zhang, Y.,Zou, A.,Emmett, M.R.,Marshall, A.G.,Zhang, H.M.,Demetri, G.D.
KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.
Proc.Natl.Acad.Sci.USA, 106:1542-1547, 2009

PubMed Abstract: Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib mesylate and sunitinib malate in GIST patients has been linked to their inhibition of these mutant KIT proteins. However, patients on imatinib can acquire secondary KIT mutations that render the protein insensitive to the inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant mutants, although a subset that resides in the activation loop, including D816H/V, remains resistant. Biochemical and structural studies were undertaken to determine the molecular basis of sunitinib resistance. Our results show that sunitinib targets the autoinhibited conformation of WT KIT and that the D816H mutant undergoes a shift in conformational equilibrium toward the active state. These findings provide a structural and enzymologic explanation for the resistance profile observed with the KIT inhibitors. Prospectively, they have implications for understanding oncogenic kinase mutants and for circumventing drug resistance.

PubMed: 19164557
DOI: 10.1073/pnas.0812413106

Experimental method

X-RAY DIFFRACTION (2.6 Å)