PDBsum entry 2vwe

Immune system

PDB id: 2vwe

Contents

Protein chains

98 a.a. *

214 a.a. *

219 a.a. *

* Residue conservation analysis

PDB id:

2vwe

Name:

Immune system

Title:

Crystal structure of vascular endothelial growth factor-b in complex with a neutralizing antibody fab fragment

Structure:

Vascular endothelial growth factor b. Chain: a, b. Synonym: vegf-b, vegf-related factor, vrf, vascular endothelial growth factor-b. Engineered: yes. Anti-vegf-b monoclonal antibody. Chain: c, j. Anti-vegf-b monoclonal antibody. Chain: e, l

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. Mouse. Organism_taxid: 10090. Organism_taxid: 10090

Resolution:

3.40Å R-factor: 0.286 R-free: 0.310

Authors:

P.Leonard,P.D.Scotney,T.Jabeen,S.Iyer,L.J.Fabri,A.D.Nash,K.R.Acharya

Key ref:

P.Leonard et al. (2008). Crystal structure of vascular endothelial growth factor-B in complex with a neutralising antibody Fab fragment. J Mol Biol, 384, 1203-1217. PubMed id: 18930733 DOI: 10.1016/j.jmb.2008.09.076

Date:

23-Jun-08 Release date: 04-Nov-08

Protein chains

P49765  (VEGFB_HUMAN) -  Vascular endothelial growth factor B from Homo sapiens

Seq: 207 a.a.

Struc: 98 a.a.

Protein chains

No UniProt id for this chain

Struc: 214 a.a.

Protein chains

No UniProt id for this chain

Struc: 219 a.a.

DOI no: 10.1016/j.jmb.2008.09.076

J Mol Biol 384:1203-1217 (2008)

PubMed id: 18930733

Crystal structure of vascular endothelial growth factor-B in complex with a neutralising antibody Fab fragment.

P.Leonard, P.D.Scotney, T.Jabeen, S.Iyer, L.J.Fabri, A.D.Nash, K.R.Acharya.

ABSTRACT

Vascular endothelial growth factor (VEGF) B effects blood vessel formation by binding to VEGF receptor 1. To study the specifics of the biological profile of VEGF-B in both physiological and pathological angiogenesis, a neutralising anti-VEGF-B antibody (2H10) that functions by inhibiting the binding of VEGF-B to VEGF receptor 1 was developed. Here, we present the structural features of the 'highly ordered' interaction of the Fab fragment of this antibody (Fab-2H10) with VEGF-B. Two molecules of Fab-2H10 bind to symmetrical binding sites located at each pole of the VEGF-B homodimer, giving a unique U-shaped topology to the complex that has not been previously observed in the VEGF family. VEGF-B residues essential for binding to the antibody are contributed by both monomers of the cytokine. Our detailed analysis reveals that the neutralising effect of the antibody occurs by virtue of the steric hindrance of the receptor-binding interface. These findings suggest that functional complementarity between VEGF-B and 2H10 can be harnessed both in analysing the therapeutic potential of VEGF-B and as an antagonist of receptor activation.

Selected figure(s)

Figure 3.
Fig. 3. (a) Stereoview of the C^α superposition of VEGF-B[10–108] in complex with Fab (green) on VEGF-A[9–109] (orange) and PlGF (blue) in complex with VEGFR-1. The N-termini and C-termini are indicated. The loop regions showing conformational changes are indicated. The figure was drawn using PyMOL.^13 (b) Sequence alignment of VEGF-B[10–108], VEGF-A[9–109], and PlGF indicating the regions binding to the antibody and VEGFR-1. The receptor-binding residues identified in the proposed model of VEGF-B[10–108] in complex with VEGFR-1 are also shown. The residues interacting with Fab are shown in blue, and the residues interacting with the receptor are shown in green. Residues from one monomer are underlined and shown in boldface; others are shown in boldface only. Residue numbering at the top refers to VEGF-A and VEGF-B, and that at the bottom refers to PlGF.

Figure 4.
Fig. 4. (a) Surface representation of the cavity formed by residues of VEGF-B[10–108] at the centre of the interface. Tyr96 from the heavy chain binds to this cavity and forms a stacking interaction with Tyr21 and Pro62 of VEGF. Residues from the heavy chain are represented in blue; VEGF residues are represented in green (monomer A) and red (monomer B). The figure was drawn using the program PyMOL.^13 (b) The binding interface illustrating the various structural elements of VEGF-B10[–]108 in contact with the antibody surface. Fab-2H10 is represented as a pale yellow surface, with residues from the different CDRs shown as ball-and-stick representation in green. The ribbon representation of VEGF-B is shown in gray, with its contributing residues shown as ball-and-stick representation in orange. Please refer to Table 3 for further details. (c) The backbone tracing of the complex of VEGF-B[10–108] with Fab-2H10, and of the complexes of VEGF-A[8–109] with Fab-12, Fab-Y0317, Fab-B20-4, and Fab-G6. The VEGF dimer is shown in green and red; the light and heavy chains of Fab fragments are represented in blue and gray, respectively. The figure was generated using Swiss-PdbViewer.^32 (d) Surface representation of the structural epitopes on VEGF-B[10–108], VEGF-A[8–109], and PlGF dimers for Fab-2H10, VEGFR-1, Fab-12, Fab-Y0317, Fab-G6, and Fab-B20-4. Each panel represents the top view of the binding epitope on different growth factors for their respective complexes. The orientation for each panel has been optimised to illustrate the contact residues in the best possible way. The ligand surface is represented in gray. Contact residues are colour-coded according to the type of interactions. Residues involved in nonpolar interactions are shown in green, uncharged polar interactions are shown in yellow, and electrostatic interactions are shown in blue (positively charged) and red (negatively charged).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 384, 1203-1217) copyright 2008.

Figures were selected by an automated process.