PDBsum entry 1agw

Protein kinase

PDB id: 1agw

Contents

Protein chains

278 a.a. *

Ligands

SU2 ×2

Waters ×234

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors.

Authors

M.Mohammadi, G.Mcmahon, L.Sun, C.Tang, P.Hirth, B.K.Yeh, S.R.Hubbard, J.Schlessinger.

Ref.

Science, 1997, 276, 955-960. [DOI no: 10.1126/science.276.5314.955]

PubMed id

9139660

Abstract

A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis.

Figure 3.
Fig. 3. 2F[o] F[c] electron density maps computed after simulated annnealing (1000 K) with the inhibitors omitted from the atomic models. Carbon atoms are colored yellow, oxygen atoms red, and nitrogen atoms blue. The red spheres represent water molecules. Maps are^ contoured at 1 . (A) Map of FGFR1K-SU4984 computed at 2.4^ Å resolution. (B) Map of FGFR1K-SU5402 computed at 2.5^ Å resolution. Figure prepared with SETOR (34).

Figure 5.
Fig. 5. Stereoviews of the inhibitor binding sites. The side chains of residues that interact with the inhibitors are shown. Carbon atoms of the inhibitor and FGFR1K are green and orange, respectively; oxygen atoms are red and nitrogen atoms are blue. Coloring of^ the backbone representation is the same as in Fig. 4. Selected^ hydrogen bonds are shown as black lines. (A) FGFR1K-SU4984. (B) FGFR1K-SU5402.

The above figures are reprinted by permission from the AAAs: Science (1997, 276, 955-960) copyright 1997.

Secondary reference #1

Title

Structure of the fgf receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism.

Authors

M.Mohammadi, J.Schlessinger, S.R.Hubbard.

Ref.

Cell, 1996, 86, 577-587. [DOI no: 10.1016/S0092-8674(00)80131-2]

PubMed id

8752212

Figure 1.
Figure 1. Electon Density Maps Near the FGFR1K Active Site(A) Stereo view of a 2F[o]-F[c] electron density map computed at 2.0 Å resolution and contoured at 1σ. Superimposed is the refined atomic model. Carbon atoms are colored green, oxygen atoms red, and nitrogen atoms blue. The red spheres represent water molecules.(B) 2F[o]-F[c] simulated annealing omit map of the AMP-PCP electron density computed at 2.3 Å resolution and contoured at 1σ. Coloring as in (A) with phosphorus atoms colored purple. The γ-phosphate group is disordered and therefore not shown.(A) and (B) prepared with SETOR ([10]).

Figure 6.
Figure 6. Autophosphorylation and Mutation Sites(A) The positions of the tyrosine autophosphorylation sites of FGFR1K are mapped onto a backbone representation (semitransparent) of FGFR1K. The view is approximately the same as in Figure 2A.(B) The sites of mutations in C. elegans EGL-15 and human FGFR3 that lead to developmental disorders are mapped onto FGFR1K. The side chains of the corresponding FGFR1 residues are shown. The EGL-15 Trp-930→Opal substitution results in truncation of the cytoplasmic domain in αI. The corresponding residues in FGFR1K that would be deleted are represented in red.(A) and (B) prepared with GRASP.

The above figures are reproduced from the cited reference with permission from Cell Press