PDBsum entry 2r4b

Transferase

PDB id: 2r4b

Contents

Protein chains

292 a.a. *

Ligands

GW7 ×2

Waters ×137

* Residue conservation analysis

PDB id:

2r4b

Name:

Transferase

Title:

Erbb4 kinase domain complexed with a thienopyrimidine inhibitor

Structure:

Receptor tyrosine-protein kinase erbb-4. Chain: a, b. Fragment: kinase domain. Synonym: p180erbb4, tyrosine kinase-type cell surface receptor her4. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: erbb4, her4. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.40Å R-factor: 0.209 R-free: 0.263

Authors:

L.M.Shewchuk,D.E.Uehling

Key ref:

E.R.Wood et al. (2008). 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 U S A, 105, 2773-2778. PubMed id: 18287036 DOI: 10.1073/pnas.0708281105

Date:

31-Aug-07 Release date: 18-Mar-08

Protein chains

Q15303  (ERBB4_HUMAN) -  Receptor tyrosine-protein kinase erbB-4 from Homo sapiens

Seq: 1308 a.a.

Struc: 292 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1073/pnas.0708281105

Proc Natl Acad Sci U S A 105:2773-2778 (2008)

PubMed id: 18287036

6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.

E.R.Wood, L.M.Shewchuk, B.Ellis, P.Brignola, R.L.Brashear, T.R.Caferro, S.H.Dickerson, H.D.Dickson, K.H.Donaldson, M.Gaul, R.J.Griffin, A.M.Hassell, B.Keith, R.Mullin, K.G.Petrov, M.J.Reno, D.W.Rusnak, S.M.Tadepalli, J.C.Ulrich, C.D.Wagner, D.E.Vanderwall, A.G.Waterson, J.D.Williams, W.L.White, D.E.Uehling.

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.

Selected figure(s)

Figure 3.
X-ray crystal structure of thienopyrimidine 6 in ErbB-4. (A) Overlay of the ErbB-4 complexed with 6 (green) and EGFR complexed with lapatinib (yellow). (B) Overlay of the active sites of ErbB-4 (green) and EGFR (yellow). The covalent bond between ErbB-4 and 6 is shown as a dotted green line. The location of a hydrogen bond between the pyrimidine N1 of 6 and the hinge region of ErbB-4 is shown by a dashed line. (C) Omit map density for the ErbB-4 inhibitor complex contoured at 1 sigma.

Figure 4.
Proposed mechanism of covalent modification of pyrrolidine 8 with EGFR.

Figures were selected by an automated process.