PDBsum entry 2x1w

Hormone/signaling protein

PDB id: 2x1w

Contents

Protein chains

98 a.a. *

196 a.a. *

179 a.a. *

193 a.a. *

Ligands

NAG-NAG-BMA ×9

NAG-NAG ×4

NAG ×7

Metals

_CS ×2

Waters ×177

* Residue conservation analysis

PDB id:

2x1w

Name:

Hormone/signaling protein

Title:

Crystal structure of vegf-c in complex with domains 2 and 3 of vegfr2

Structure:

Vascular endothelial growth factor c. Chain: a, b, c, d. Fragment: vegf homology domain, residues 112-215. Synonym: vegf-c, vascular endothelial growth factor-related protein, vrp, flt4 ligand, flt4-l. Engineered: yes. Mutation: yes. Vascular endothelial growth factor receptor 2. Chain: l, m, n, o.

Source:

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

Resolution:

2.70Å R-factor: 0.230 R-free: 0.280

Authors:

V.M.Leppanen,A.E.Prota,M.Jeltsch,A.Anisimov,N.Kalkkinen,T.Strandin, H.Lankinen,A.Goldman,K.Ballmer-Hofer,K.Alitalo

Key ref:

V.M.Leppänen et al. (2010). Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proc Natl Acad Sci U S A, 107, 2425-2430. PubMed id: 20145116 DOI: 10.1073/pnas.0914318107

Date:

08-Jan-10 Release date: 09-Mar-10

Protein chains

P49767  (VEGFC_HUMAN) -  Vascular endothelial growth factor C from Homo sapiens

Seq: 419 a.a.

Struc: 98 a.a.*

Protein chains

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

Seq: 1356 a.a.

Struc: 196 a.a.

Protein chain

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

Seq: 1356 a.a.

Struc: 179 a.a.

Protein chain

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

Seq: 1356 a.a.

Struc: 193 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains L, M, N, O: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = NAG) matches with 41.38% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1073/pnas.0914318107

Proc Natl Acad Sci U S A 107:2425-2430 (2010)

PubMed id: 20145116

Structural determinants of growth factor binding and specificity by VEGF receptor 2.

V.M.Leppänen, A.E.Prota, M.Jeltsch, A.Anisimov, N.Kalkkinen, T.Strandin, H.Lankinen, A.Goldman, K.Ballmer-Hofer, K.Alitalo.

ABSTRACT

Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel formation through activation of three receptor tyrosine kinases, VEGFR-1, -2, and -3. The extracellular domain of VEGF receptors consists of seven immunoglobulin homology domains, which, upon ligand binding, promote receptor dimerization. Dimerization initiates transmembrane signaling, which activates the intracellular tyrosine kinase domain of the receptor. VEGF-C stimulates lymphangiogenesis and contributes to pathological angiogenesis via VEGFR-3. However, proteolytically processed VEGF-C also stimulates VEGFR-2, the predominant transducer of signals required for physiological and pathological angiogenesis. Here we present the crystal structure of VEGF-C bound to the VEGFR-2 high-affinity-binding site, which consists of immunoglobulin homology domains D2 and D3. This structure reveals a symmetrical 22 complex, in which left-handed twisted receptor domains wrap around the 2-fold axis of VEGF-C. In the VEGFs, receptor specificity is determined by an N-terminal alpha helix and three peptide loops. Our structure shows that two of these loops in VEGF-C bind to VEGFR-2 subdomains D2 and D3, while one interacts primarily with D3. Additionally, the N-terminal helix of VEGF-C interacts with D2, and the groove separating the two VEGF-C monomers binds to the D2/D3 linker. VEGF-C, unlike VEGF-A, does not bind VEGFR-1. We therefore created VEGFR-1/VEGFR-2 chimeric proteins to further study receptor specificity. This biochemical analysis, together with our structural data, defined VEGFR-2 residues critical for the binding of VEGF-A and VEGF-C. Our results provide significant insights into the structural features that determine the high affinity and specificity of VEGF/VEGFR interactions.

Selected figure(s)

Figure 1.
Structure of the VEGF-C/VEGFR-2D23 complex in a cartoon representation. The VEGF-C homodimer is shown in orange and green, and the two VEGFR-2 receptor chains are colored in light blue. The sugar moieties and the disulfide bonds are shown in purple and yellow sticks, respectively. VEGF-C binds to the VEGFR-2 interface between domains 2 and 3.

Figure 2.
Interface between VEGF-C and VEGFR-2. (A) VEGF-C binding interface on VEGFR-2. VEGFR-2 is shown as a cartoon representation with the VEGF-C binding key residues highlighted in sticks and labeled. (B) An overview of the VEGF-C/VEGFR-2D23 site 1 interface, with VEGF-C monomer A colored in green and VEGF-C residues at the interface labeled. VEGFR-2 charge distribution shown as a surface potential model. (C) The same as in (B) for the site 2 interface with VEGF-C monomer B in orange and the monomer 2 key residues labeled. (D) VEGF-C Asp123 interactions with VEGFR-2. Hydrogen bonds and salt bridges are shown in gray dashed lines. (E) VEGF-C Glu169 interactions with VEGFR-2 as in (D). (F) VEGF-C Thr148 and Asn149 interactions with VEGFR-2 as in (D).

Figures were selected by the author.