PDBsum entry 4wun

Transferase/transferase inhibitor

PDB id: 4wun

Contents

Protein chains

282 a.a.

268 a.a.

Ligands

66T ×2

Waters ×207

PDB id:

4wun

Name:

Transferase/transferase inhibitor

Title:

Structure of fgfr1 in complex with azd4547 (n-{3-[2-(3,5- dimethoxyphenyl)ethyl]-1h-pyrazol-5-yl}-4-[(3r,5s)-3,5- dimethylpiperazin-1-yl]benzamide) at 1.65 angstrom

Structure:

Fibroblast growth factor receptor 1. Chain: a, b. Fragment: unp residues 311-490. Synonym: fgfr-1,basic fibroblast growth factor receptor 1,bfgf-r-1, fms-like tyrosine kinase 2,flt-2,n-sam,proto-oncogenE C-fgr. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr1, bfgfr, cek, fgfbr, flg, flt2, hbgfr. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.65Å R-factor: 0.226 R-free: 0.247

Authors:

C.J.Squire,C.J.Yosaatmadja

Key ref:

Y.Yosaatmadja et al. (2015). The 1.65 Å resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition. Acta Crystallogr D Biol Crystallogr, 71, 525-533. PubMed id: 25760602 DOI: 10.1107/S1399004714027539

Date:

02-Nov-14 Release date: 19-Nov-14

Protein chain

P11362  (FGFR1_HUMAN) -  Fibroblast growth factor receptor 1 from Homo sapiens

Seq: 822 a.a.

Struc: 282 a.a.*

Protein chain

P11362  (FGFR1_HUMAN) -  Fibroblast growth factor receptor 1 from Homo sapiens

Seq: 822 a.a.

Struc: 268 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: 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: 10.1107/S1399004714027539

Acta Crystallogr D Biol Crystallogr 71:525-533 (2015)

PubMed id: 25760602

The 1.65 Å resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition.

Y.Yosaatmadja, A.V.Patterson, J.B.Smaill, C.J.Squire.

ABSTRACT

The fibroblast growth factor receptor (FGFR) family are expressed widely in normal tissues and play a role in tissue repair, inflammation, angiogenesis and development. However, aberrant signalling through this family can lead to cellular proliferation, evasion of apoptosis and induction of angiogenesis, which is implicated in the development of many cancers and also in drug resistance. The high frequency of FGFR amplification or mutation in multiple cancer types is such that this family has been targeted for the discovery of novel, selective drug compounds, with one of the most recently discovered being AZD4547, a subnanomolar (IC50) FGFR1 inhibitor developed by AstraZeneca and currently in clinical trials. The 1.65 Å resolution crystal structure of AZD4547 bound to the kinase domain of FGFR1 has been determined and reveals extensive drug-protein interactions, an integral network of water molecules and the tight closure of the FGFR1 P-loop to form a long, narrow crevice in which the AZD4547 molecule binds.