PDBsum entry: 1ry7

Growth factor/growth factor receptor

PDB-id: 1ry7

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

Main view

Contents

Description

Header details

Header records

References

PROCHECK

Protein chains

151 a.a. *

213 a.a. *

* Residue conservation analysis

Tools

Clefts Calculation

Bottom view	Right view

PDB id:

1ry7

Name:

Growth factor/growth factor receptor

Title:

Crystal structure of the 3 ig form of fgfr3c in complex with fgf1

Structure:

Heparin-binding growth factor 1. Chain: a. Fragment: fgf1. Synonym: hbgf-1. Acidic fibroblast growth factor. Afgf. Beta-endothelial cell growth factor. Ecgf-beta. Engineered: yes. Fibroblast growth factor receptor 3. Chain: b. Fragment: fgfr-3c.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgf1. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: fgfr3c. Expression_system_taxid: 562

Biological unit:

Dimer (from PQS)

UniProt:

Chain A: P05230 (FGF1_HUMAN)

Seq:	155 a.a.
Struc:	151 a.a.

Chain B: P22607 (FGFR3_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

Struc:

Seq:

806 a.a.

Struc:

213 a.a.

Key:	PfamA domain	PfamB domain
Secondary structure	CATH domain

Enzyme class:

Chain B: E.C.2.7.10.1   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

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

Resolution:

3.20Å

R-factor:

0.277

R-free:

0.341

Authors:

S.K.Olsen,O.A.Ibrahimi,A.Raucci,F.Zhang,A.V.Eliseenkova, A.Yayon,C.Basilico,R.J.Linhardt,J.Schlessinger,M.Mohammadi

Key ref:

S.K.Olsen et al. (2004). Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity.. Proc Natl Acad Sci U S A, 101, 935-940. [PubMed id: 14732692] [DOI: 10.1073/pnas.0307287101]

Date:

19-Dec-03

Release date:

10-Feb-04

Related entries:

1djs
crystal structure of fgf1-fgfr2c complex
1evt
crystal structure of fgf1-fgfr1c complex
1nun
crystal structure of fgf10-fgfr2b complex

Quick_links

Procheck

Clefts

Surface

Key reference

DOI no: 10.1073/pnas.0307287101

Proc Natl Acad Sci U S A 101:935-940 (2004)

PubMed id: 14732692

Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity.

S.K.Olsen, O.A.Ibrahimi, A.Raucci, F.Zhang, A.V.Eliseenkova, A.Yayon, C.Basilico, R.J.Linhardt, J.Schlessinger, M.Mohammadi.

ABSTRACT

The prototypical fibroblast growth factor receptor (FGFR) extracellular domain consists of three Ig domains (D1-D3) of which the two membrane-proximal D2 and D3 domains and the interconnecting D2-D3 linker bear the determinants of ligand binding and specificity. In contrast, D1 and the D1-D2 linker are thought to play autoinhibitory roles in FGFR regulation. Here, we report the crystal structure of the three-Ig form of FGFR3c in complex with FGF1, an FGF that binds promiscuously to each of the seven principal FGFRs. In this structure, D1 and the D1-D2 linker are completely disordered, demonstrating that these regions are dispensable for FGF binding. Real-time binding experiments using surface plasmon resonance show that relative to two-Ig form, the three-Ig form of FGFR3c exhibits lower affinity for both FGF1 and heparin. Importantly, we demonstrate that this autoinhibition is mediated by intramolecular interactions of D1 and the D1-D2 linker with the minimal FGF and heparin-binding D2-D3 region. As in the FGF1-FGFR2c structure, but not the FGF1-FGFR1c structure, the alternatively spliced betaC'-betaE loop is ordered and interacts with FGF1 in the FGF1-FGFR3c structure. However, in contrast to the FGF1-FGFR2c structure in which the betaC'-betaE loop interacts with the beta-trefoil core region of FGF1, in the FGF1-FGFR3c structure, this loop interacts extensively with the N-terminal region of FGF1, underscoring the importance of the FGF1 N terminus in conferring receptor-binding affinity and promiscuity. Importantly, comparison of the three FGF1-FGFR structures shows that the flexibility of the betaC'-betaE loop is a major determinant of ligand-binding specificity and promiscuity.

Selected figure(s)

Figure 1.
Fig. 1. The FGFR3c-FGF1 structure. (A) A ribbon representation of the FGFR3c-FGF1 complex. FGF1 is orange, FGFR3c D2 is green, D3 is cyan, and the D2-D3 linker is black. The alternatively spliced C-terminal half of D3 is purple. The N and C termini of FGF1 are labeled NT and CT, respectively. The FGF1 N-terminal region not included in the truncated FGF1 construct used in the FGFR1c and FGFR2c structures is gray. (Inset) Protein from FGF1-FGFR3c crystals is indistinguishable from the freshly purified complex. SDS/PAGE analysis of the purified three-Ig form FGFR3c-FGF1 complex (1), the purified two-Ig form FGFR3c-FGF1 complex (2), the protein solution from a FGF1-FGFR3c crystal containing hanging drop (3), and dissolved FGF1-FGFR3c crystals (4) (washed twice). Lanes with molecular mass markers are labeled M, and selected molecular masses are labeled. (B) Structure-based sequence alignment of Ig domain 3 from human FGFRs. The sequence alignment was performed by using CLUSTALW (28). The location and length of the strands are shown on top of the sequence alignment. Note that the C' strand of FGFR3c terminates two residues earlier than those of FGFR1c and FGFR2c, and, therefore, the C'- E loop of FGFR3 is 12 residues long (residues 310-322). The different lengths of the C'- E loops of FGFR1c and FGFR2c from the FGF1-FGFR structures are indicated by boxes within the alignment. A period indicates sequence identity to FGFR3c. A dash represents a gap introduced to optimize the alignment. The alternatively spliced C-terminal half of D3 is marked by red arrows. FGFR3c residues that interact with FGF1 are red. FGFR1c and FGFR2c residues that interact with FGF in other crystal structures are cyan. (C) Superimposition of FGFR3c and FGFR2c D3. The C^ trace of FGFR2c D3 from the FGFR2c-FGF1 structure (cyan) was superimposed onto the C^trace of FGFR3c D3 from the FGFR3c-FGF1 structure (orange; rms deviation = 0.831 Å). Residues corresponding to the C- C' and C'- E loops were not included in the superimposition. The B'- C, C'- E, and F- G loops of the D3s are marked by an arrowhead. (D) Interactions between the FGF1 N terminus and D3 in the FGFR3c-FGF1 structure. Colors are as in A. Selected residues are labeled and are rendered in a stick format. This figure was created by using the program PYMOL (29).

Figure 3.
Fig. 3. D1 and the D1-D2 linker negatively regulate ligand- and heparin-binding affinity of FGFR3c. (A and B) Sensorgrams of the two-versus three-Ig form of FGFR3c binding to full-length FGF1. Analyte concentrations are colored as follows: purple (1.6 µM), green (0.8 µM), red (0.4 µM), blue (0.2µM), and gray (0.1 µM). (C and D) Sensorgrams of the two-versus three-Ig form of FGFR3c binding to heparin. Analyte concentrations are colored as follows: purple (5 µM), yellow (2.5 µM), orange (1.25 µM), red (0.625 µM), and cyan (0.313 µM). (E) Sensorgram of D1+ binding to the two-Ig form of FGFR3c. Analyte concentrations are colored as follows: purple (10 µM), pink (5 µM), yellow (2.5 µM), and cyan (1 µM).

Figures were selected by the author.