2R4B

ErbB4 kinase domain complexed with a thienopyrimidine inhibitor

Summary for 2R4B

• Entry DOI: 10.2210/pdb2r4b/pdb
• Descriptor: Receptor tyrosine-protein kinase erbB-4, N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-ethylthieno[3,2-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: erb, kinase, atp-binding, glycoprotein, membrane, nucleotide-binding, phosphorylation, receptor, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein. ERBB4 intracellular domain: Nucleus: Q15303
• Total number of polymer chains: 2
• Total formula weight: 73935.01

Authors

Shewchuk, L.M.,Uehling, D.E. (deposition date: 2007-08-31, release date: 2008-03-18, Last modification date: 2024-10-16)

Primary citation

Wood, E.R.,Shewchuk, L.M.,Ellis, B.,Brignola, P.,Brashear, R.L.,Caferro, T.R.,Dickerson, S.H.,Dickson, H.D.,Donaldson, K.H.,Gaul, M.,Griffin, R.J.,Hassell, A.M.,Keith, B.,Mullin, R.,Petrov, K.G.,Reno, M.J.,Rusnak, D.W.,Tadepalli, S.M.,Ulrich, J.C.,Wagner, C.D.,Vanderwall, D.E.,Waterson, A.G.,Williams, J.D.,White, W.L.,Uehling, D.E.
6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.
Proc.Natl.Acad.Sci.Usa, 105:2773-2778, 2008

PubMed Abstract: Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.

PubMed: 18287036
DOI: 10.1073/pnas.0708281105

Experimental method

X-RAY DIFFRACTION (2.4 Å)