2JIV

Crystal structure of EGFR kinase domain T790M mutation in compex with HKI-272

Summary for 2JIV

• Entry DOI: 10.2210/pdb2jiv/pdb
• Related: 1DNQ 1DNR 1IVO 1M14 1M17 1MOX 1NQL 1XKK 1YY9 1Z9I 2GS2 2GS7 2ITN 2ITO 2ITP 2ITQ 2ITT 2ITU 2ITV 2ITW 2ITX 2ITY 2ITZ 2J5E 2J5F 2J6M 2JIT 2JIU
• Descriptor: EPIDERMAL GROWTH FACTOR RECEPTOR, N-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)butanamide, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: hki272, hki-272, receptor, cell cycle, atp-binding, transferase, tyrosine-protein kinase, transmembrane, phosphorylation, disease mutation, nucleotide-binding, anti-oncogene, epidermal growth factor
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 2
• Total formula weight: 76031.63

Authors

Yun, C.-H.,Mengwasser, K.E.,Toms, A.V.,Li, Y.,Woo, M.S.,Greulich, H.,Wong, K.-K.,Meyerson, M.,Eck, M.J. (deposition date: 2007-07-02, release date: 2008-01-22, Last modification date: 2024-11-06)

Primary citation

Yun, C.-H.,Mengwasser, K.E.,Toms, A.V.,Woo, M.S.,Greulich, H.,Wong, K.-K.,Meyerson, M.,Eck, M.J.
The T790M Mutation in Egfr Kinase Causes Drug Resistance by Increasing the Affinity for ATP.
Proc.Natl.Acad.Sci.USA, 105:2070-, 2008

PubMed Abstract: Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M. Threonine 790 is the "gatekeeper" residue, an important determinant of inhibitor specificity in the ATP binding pocket. The T790M mutation has been thought to cause resistance by sterically blocking binding of TKIs such as gefitinib and erlotinib, but this explanation is difficult to reconcile with the fact that it remains sensitive to structurally similar irreversible inhibitors. Here, we show by using a direct binding assay that T790M mutants retain low-nanomolar affinity for gefitinib. Furthermore, we show that the T790M mutation activates WT EGFR and that introduction of the T790M mutation increases the ATP affinity of the oncogenic L858R mutant by more than an order of magnitude. The increased ATP affinity is the primary mechanism by which the T790M mutation confers drug resistance. Crystallographic analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272, and also suggests a structural mechanism for catalytic activation. We conclude that the T790M mutation is a "generic" resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.

PubMed: 18227510
DOI: 10.1073/PNAS.0709662105

Experimental method

X-RAY DIFFRACTION (3.5 Å)