PDBsum entry 4bsk

Transferase/hormone

PDB id: 4bsk

Contents

Protein chains

172 a.a.

98 a.a.

Ligands

NAG-NAG

NAG ×4

PDB id:

4bsk

Name:

Transferase/hormone

Title:

Crystal structure of vegf-c in complex with vegfr-3 domains d1-2

Structure:

Vascular endothelial growth factor receptor 3. Chain: a. Fragment: ligand-binding domains d1-2, residues 23-229. Synonym: vegfr-3, fms-like tyrosine kinase 4, flt-4, tyrosine-protein kinase receptor flt4, vegfr-3. Engineered: yes. Other_details: covalent n-glycosylation in asn33, asn104 and asn166. Vascular endothelial growth factor c. Chain: c.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

4.20Å R-factor: 0.338 R-free: 0.372

Authors:

V.M.Leppanen,D.Tvorogov,K.Kisko,A.E.Prota,M.Jeltsch,A.Anisimov, S.Markovic-Mueller,E.Stuttfeld,K.N.Goldie,K.Ballmer-Hofer,K.Alitalo

Key ref:

V.M.Leppänen et al. (2013). Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc Natl Acad Sci U S A, 110, 12960-12965. PubMed id: 23878260 DOI: 10.1073/pnas.1301415110

Date:

10-Jun-13 Release date: 31-Jul-13

Protein chain

P35916  (VGFR3_HUMAN) -  Vascular endothelial growth factor receptor 3 from Homo sapiens

Seq: 1363 a.a.

Struc: 172 a.a.

Protein chain

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

Seq: 419 a.a.

Struc: 98 a.a.*

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

Enzyme reactions

• Enzyme class: Chain A: 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.1301415110

Proc Natl Acad Sci U S A 110:12960-12965 (2013)

PubMed id: 23878260

Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation.

V.M.Leppänen, D.Tvorogov, K.Kisko, A.E.Prota, M.Jeltsch, A.Anisimov, S.Markovic-Mueller, E.Stuttfeld, K.N.Goldie, K.Ballmer-Hofer, K.Alitalo.

ABSTRACT

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes. VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis. The extracellular domain of VEGFRs consists of seven Ig homology domains; domains 1-3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4-7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation. Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer. The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5. Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation. A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding. A structural model of the VEGF-C/VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7. Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs.