5fv1

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Crystal structure of hVEGF in complex with VK domain antibody

Structural highlights

5fv1 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

VEGFA_HUMAN Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:603933. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis.

Function

VEGFA_HUMAN Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.[1] [2] [3]

Publication Abstract from PubMed

A potent VEGF inhibitor with novel antibody architecture and antigen binding mode has been developed. The molecule, hereafter referred to as VEGF dual dAba (domain antibody), was evaluated in vitro for binding to VEGF and for potency in VEGF driven models and compared with other anti-VEGF biologics that have been used in ocular anti-angiogenic therapeutic regimes. VEGF dual dAb is more potent than bevacizumab and ranibizumab for VEGF binding and inhibition of VEGF RBAb (receptor binding assay) formats and when compared using in vitro models of angiogenesis; and displays comparable inhibition to aflibercept, (Eylea). VEGF dual dAb is dimeric and each monomer contains two distinct anti-VEGF domain antibodies attached via linkers to a human IgG1 Fc domain. Mechanistically, the enhanced in vitro potency of VEGF dual dAb in comparison to other anti-VEGF biologics can be explained by increased binding stoichiometry. A consistent model of the target engagement has been built based on the X-ray complexes of each of the two isolated domain antibodies with the VEGF antigen.

Novel interaction mechanism of a domain antibody based inhibitor of human vascular endothelial growth factor with greater potency than ranibizumab and bevacizumab and improved capacity over aflibercept.,Walker A, Chung CW, Neu M, Burman M, Batuwangala T, Jones G, Tang CM, Steward M, Mullin M, Tournier N, Lewis A, Korczynska J, Chung V, Catchpole I J Biol Chem. 2016 Jan 4. pii: jbc.M115.691162. PMID:26728464[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
2 reviews cite this structure
Antigen recognition by single-domain antibodies: structural latitudes and constraints.
Henry et al. (2018)
1 more
9 other articles
No citations found

See Also

References

  1. ↑ Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. FASEB J. 2001 Jul;15(9):1667-9. PMID:11427521
  2. ↑ Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, Cui TG, Sugiono M, Waine E, Perrin R, Foster R, Digby-Bell J, Shields JD, Whittles CE, Mushens RE, Gillatt DA, Ziche M, Harper SJ, Bates DO. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res. 2004 Nov 1;64(21):7822-35. PMID:15520188 doi:10.1158/0008-5472.CAN-04-0934
  3. ↑ Dixelius J, Olsson AK, Thulin A, Lee C, Johansson I, Claesson-Welsh L. Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein. Cancer Res. 2006 Feb 15;66(4):2089-97. PMID:16489009 doi:10.1158/0008-5472.CAN-05-2217
  4. ↑ Walker A, Chung CW, Neu M, Burman M, Batuwangala T, Jones G, Tang CM, Steward M, Mullin M, Tournier N, Lewis A, Korczynska J, Chung V, Catchpole I. Novel interaction mechanism of a domain antibody based inhibitor of human vascular endothelial growth factor with greater potency than ranibizumab and bevacizumab and improved capacity over aflibercept. J Biol Chem. 2016 Jan 4. pii: jbc.M115.691162. PMID:26728464 doi:http://dx.doi.org/10.1074/jbc.M115.691162

Contents


PDB ID 5fv1

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OCA

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