PDBsum entry: 2fgi

Transferase

PDB-id: 2fgi

Biological unit* = asymmetric unit,
as shown
(*as deduced by PQS)

Contents

Description

Header details

Header records

References

PROCHECK

Protein chains

274 a.a. *

Ligands

PD1 ×2

Waters ×191

* Residue conservation analysis

Tools

Clefts Calculation

PDB id:

2fgi

Name:

Transferase

Title:

Crystal structure of the tyrosine kinase domain of fgf receptor 1 in complex with inhibitor pd173074

Structure:

Protein (fibroblast growth factor (fgf) receptor 1). Chain: a, b. Fragment: tyrosine kinase domain. Synonym: fgfr1k. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: sf9. Cellular_location: cytoplasm. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Biological unit:

Dimer (from PQS)

UniProt:

Chains A, B: P11362 (FGFR1_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

Struc:

Seq:

822 a.a.

Struc:

274 a.a.

Key:	PfamA domain
Secondary structure	CATH domain

Enzyme class:

E.C.2.7.10.1   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate

Resolution:

2.50Å

R-factor:

0.204

R-free:

0.264

Authors:

M.Mohammadi,S.Froum,J.M.Hamby,M.Schroeder,R.L.Panek,G.H.Lu, A.V.Eliseenkova,D.Green,J.Schlessinger,S.R.Hubbard

Key ref:

M.Mohammadi et al. (1998). Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain.. EMBO J, 17, 5896-5904. [PubMed id: 9774334] [DOI: 10.1093/emboj/17.20.5896]

Date:

15-Sep-98

Release date:

13-Sep-99

Quick_links

Procheck

Clefts

Surface

Key reference

DOI no: 10.1093/emboj/17.20.5896

EMBO J 17:5896-5904 (1998)

PubMed id: 9774334

Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain.

M.Mohammadi, S.Froum, J.M.Hamby, M.C.Schroeder, R.L.Panek, G.H.Lu, A.V.Eliseenkova, D.Green, J.Schlessinger, S.R.Hubbard.

ABSTRACT

Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is an essential physiological process in development, yet also plays a major role in the progression of human diseases such as diabetic retinopathy, atherosclerosis and cancer. The effects of the most potent angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin and fibroblast growth factor (FGF) are mediated through cell surface receptors that possess intrinsic protein tyrosine kinase activity. In this report, we describe a synthetic compound of the pyrido[2,3-d]pyrimidine class, designated PD 173074, that selectively inhibits the tyrosine kinase activities of the FGF and VEGF receptors. We show that systemic administration of PD 173074 in mice can effectively block angiogenesis induced by either FGF or VEGF with no apparent toxicity. To elucidate the determinants of selectivity, we have determined the crystal structure of PD 173074 in complex with the tyrosine kinase domain of FGF receptor 1 at 2.5 A resolution. A high degree of surface complementarity between PD 173074 and the hydrophobic, ATP-binding pocket of FGF receptor 1 underlies the potency and selectivity of this inhibitor. PD 173074 is thus a promising candidate for a therapeutic angiogenesis inhibitor to be used in the treatment of cancer and other diseases whose progression is dependent upon new blood vessel formation.

Selected figure(s)

Figure 4.
Figure 4 Mode of PD 173074 binding to FGFR1K. (A) Stereo view of the PD 173074 binding pocket in FGFR1K. The side chains of residues that interact with the inhibitor are shown as well as main-chain atoms that participate in hydrogen bonding. Split-bond coloring is used with carbon atoms orange (PD 173074) or green (FGFR1K), oxygen atoms red, nitrogen atoms blue and sulfur atoms yellow. The FGFR1K main-chain representation is colored light blue for the nucleotide-binding loop, purple for the segment connecting the two kinase lobes, yellow for the catalytic loop and orange for the activation loop. Hydrogen bonds are shown as dashed lines. (B) Superposition of PD 173074 and AMP-PCP (Mohammadi et al., 1996a) bound to FGFR1K. View is approximately perpendicular to the pyrido[2,3-d]pyrimidine/adenine rings. Bonds and carbon atoms are colored orange (PD 173074), green (FGFR1K) or gray (AMP-PCP). Other atoms colored as in (A) with phosphorus atoms black. Hydrogen bonds are shown as black (AMP-PCP) or orange (PD 173074) dashed lines. Due to disorder, the phosphate of AMP-PCP is not modeled. Prepared with GRASP (Nicholls et al., 1991).

Figure 5.
Figure 5 Schematic diagram of interactions between FGFR1K and PD 173074. Shown are contacts for which the interatomic distance is 3.8 Å. Thin solid lines denote contacts involving FGFR1K side-chain atoms, and thin dotted lines denote contacts involving FGFR1K main-chain atoms. Hydrogen bonds are shown as thick gray lines. No contacts are shown for the butyl and diethylamino groups due to the relative disorder of these atoms. Et = ethyl and t-Bu = tert-butyl.

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (1998, 17, 5896-5904) copyright 1998.

Figures were selected by an automated process.