PDBsum entry 3kvq

Transferase

PDB id: 3kvq

Contents

Protein chain

82 a.a. *

Waters ×35

* Residue conservation analysis

PDB id:

3kvq

Name:

Transferase

Title:

Crystal structure of vegfr2 extracellular domain d7

Structure:

Vascular endothelial growth factor receptor 2. Chain: a. Fragment: extracellular domain 7. Synonym: vegfr-2, kinase insert domain receptor, protein-tyrosine kinase receptor flk-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: flk1, kdr, vegfr2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.70Å R-factor: 0.233 R-free: 0.296

Authors:

Y.Yang,Y.Opatowsky,P.Xie,J.Schlessinger

Key ref:

Y.Yang et al. (2010). Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling. Proc Natl Acad Sci U S A, 107, 1906-1911. PubMed id: 20080685 DOI: 10.1073/pnas.0914052107

Date:

30-Nov-09 Release date: 16-Feb-10

Protein chain

P35968  (VGFR2_HUMAN) -  Vascular endothelial growth factor receptor 2 from Homo sapiens

Seq: 1356 a.a.

Struc: 82 a.a.

Enzyme reactions

• Enzyme class: 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: 10.1073/pnas.0914052107

Proc Natl Acad Sci U S A 107:1906-1911 (2010)

PubMed id: 20080685

Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling.

Y.Yang, P.Xie, Y.Opatowsky, J.Schlessinger.

ABSTRACT

Structural analyses of the extracellular region of stem cell factor (SCF) receptor (also designated KIT) in complex with SCF revealed a sequence motif in a loop in the fourth Ig-like domain (D4) that is responsible for forming homotypic receptor contacts and for ligand-induced KIT activation and cell signaling. An identical motif was identified in the most membrane-proximal seventh Ig-like domain (D7) of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. In this report we demonstrate that ligand-induced tyrosine autophosphorylation and cell signaling via VEGFR1 or VEGFR2 harboring mutations in critical residues (Arg726 or Asp731) in D7 are strongly impaired. We also describe the crystal structure of D7 of VEGFR2 to a resolution of 2.7 A. The structure shows that homotypic D7 contacts are mediated by salt bridges and van der Waals contacts formed between Arg726 of one protomer and Asp731 of the other protomer. The structure of D7 dimer is very similar to the structure of D4 dimers seen in the crystal structure of KIT extracellular region in complex with SCF. The high similarity between VEGFR D7 and KIT D4 in both structure and function provides further evidence for common ancestral origins of type III and type V RTKs. It also reveals a conserved mechanism for RTK activation and a novel target for pharmacological intervention of pathologically activated RTKs.

Selected figure(s)

Figure 3.
Structure of VEGFR2 D7 homodimer. (A) A ribbon diagram and a transparent molecular surface of D7 homodimer structure (side view). Asp731 and Arg726 are shown as a stick model. (B) A close view of the homotypic D7 interface of the two neighboring molecules (pink and green). Salt bridges formed between Asp731 and Arg726 are shown as dashed lines. (C) Charge distribution of D7 homodimer (side view) is shown as a surface potential model (Left). View of D7 surface that mediates homotypic contacts (Right). (D) 2F[o]-F[c] electron density map contoured at 1.1σ level showing a view of the D7–D7 interface. The backbones of VEGFR D7 protomers are represented as pink and yellow tubes, respectively.

Figure 4.
Superposition of the structure of D7 of VEGFR2 with the structure of D4 of dimeric KIT-SCF complex. Overlay of VEGFR D7 structure (PDB ID code: 3KVQ) and the structure of KIT dimer in complex with SCF (PDB ID code: 2E9W) (Left). A closer view of superimposed D7 and D4 regions reveals high similarity in domain arrangement and homotypic contacts (Right). VEGFR2 D7 is illustrated in green and the EF loop is in yellow. D4 of KIT is illustrated in gray and its EF loop is in orange.

Figures were selected by an automated process.