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PDBsum entry 1vgh

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protein links
Growth factor PDB id
1vgh
Jmol
Contents
Protein chain
55 a.a. *
* Residue conservation analysis
PDB id:
1vgh
Name: Growth factor
Title: Heparin-binding domain from vascular endothelial growth factor, nmr, 20 structures
Structure: Vascular endothelial growth factor-165. Chain: a. Fragment: heparin-binding domain. Synonym: vegf-165. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
NMR struc: 20 models
Authors: W.J.Fairbrother,M.A.Champe,H.W.Christinger,B.A.Keyt, M.A.Starovasnik
Key ref:
W.J.Fairbrother et al. (1998). Solution structure of the heparin-binding domain of vascular endothelial growth factor. Structure, 6, 637-648. PubMed id: 9634701 DOI: 10.1016/S0969-2126(98)00065-3
Date:
17-Dec-97     Release date:   08-Apr-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P15692  (VEGFA_HUMAN) -  Vascular endothelial growth factor A
Seq:
Struc:
232 a.a.
55 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     heparin binding     1 term  

 

 
DOI no: 10.1016/S0969-2126(98)00065-3 Structure 6:637-648 (1998)
PubMed id: 9634701  
 
 
Solution structure of the heparin-binding domain of vascular endothelial growth factor.
W.J.Fairbrother, M.A.Champe, H.W.Christinger, B.A.Keyt, M.A.Starovasnik.
 
  ABSTRACT  
 
BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and is a potent angiogenic and vascular permeabilizing factor. VEGF is also an important mediator of pathological angiogenesis associated with cancer, rheumatoid arthritis and proliferative retinopathy. The binding of VEGF to its two known receptors, KDR and Flt-1, is modulated by cell-surface-associated heparin-like glycosaminoglycans and exogenous heparin or heparan sulfate. Heparin binding to VEGF165, the most abundantly expressed isoform of VEGF, has been localized to the carboxy-terminal 55 residues; plasmin cleavage of VEGF165 yields a homodimeric 110-residue amino-terminal receptor-binding domain (VEGF110) and two 55-residue carboxy-terminal heparin-binding fragments. The endothelial cell mitogenic potency of VEGF110 is decreased significantly relative to VEGF165, indicating that the heparin-binding domains are critical for stimulating endothelial cell proliferation. RESULTS: The solution structure of the 55-residue heparin-binding domain of VEGF165 has been solved using data from two-dimensional homonuclear and three-dimensional heteronuclear NMR spectroscopy. The structure has two subdomains, each containing two disulfide bridges and a short two-stranded antiparallel beta sheet; the carboxy-terminal subdomain also contains a short alpha helix. Hydrophobic interactions are limited to sidechains packing against the disulfide bridges. CONCLUSIONS: The heparin-binding domain of VEGF has no significant sequence or structural similarity to any known proteins and thus represents a novel heparin-binding domain. Most of the positively charged amino acid sidechains are localized on one side of the carboxy-terminal subdomain or on an adjacent disordered loop in the amino-terminal subdomain. The observed distribution of surface charges suggests that these residues constitute a heparin interaction site.
 
  Selected figure(s)  
 
Figure 7.
Figure 7. The solvent-accessible molecular surface of the minimized mean structure of VEGF[55] color coded according to electrostatic surface potential; red, -10 kT; white, 0 kT; and blue, +10 kT. The positions of charged sidechains are labeled. The two views are related by a 180 rotation about the vertical axis. The figure was produced using the program GRASP [70].
 
  The above figure is reprinted by permission from Cell Press: Structure (1998, 6, 637-648) copyright 1998.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20155389 J.A.Ji, J.Liu, S.J.Shire, T.J.Kamerzell, S.Hong, K.Billeci, Y.Shen, and Y.J.Wang (2010).
Characteristics of rhVEGF release from topical hydrogel formulations.
  Pharm Res, 27, 644-654.  
19136576 E.Kurtagic, M.P.Jedrychowski, and M.A.Nugent (2009).
Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity.
  Am J Physiol Lung Cell Mol Physiol, 296, L534-L546.  
19540581 S.M.Anderson, T.T.Chen, M.L.Iruela-Arispe, and T.Segura (2009).
The phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) by engineered surfaces with electrostatically or covalently immobilized VEGF.
  Biomaterials, 30, 4618-4628.  
18065694 E.Sulpice, J.Plouët, M.Bergé, D.Allanic, G.Tobelem, and T.Merkulova-Rainon (2008).
Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity.
  Blood, 111, 2036-2045.  
18608994 F.Mac Gabhann, and A.S.Popel (2008).
Systems biology of vascular endothelial growth factors.
  Microcirculation, 15, 715-738.  
18220500 R.S.Apte (2008).
Pegaptanib sodium for the treatment of age-related macular degeneration.
  Expert Opin Pharmacother, 9, 499-508.  
18923433 S.J.Harper, and D.O.Bates (2008).
VEGF-A splicing: the key to anti-angiogenic therapeutics?
  Nat Rev Cancer, 8, 880-887.  
17989695 B.A.Appleton, P.Wu, J.Maloney, J.Yin, W.C.Liang, S.Stawicki, K.Mortara, K.K.Bowman, J.M.Elliott, W.Desmarais, J.F.Bazan, A.Bagri, M.Tessier-Lavigne, A.W.Koch, Y.Wu, R.J.Watts, and C.Wiesmann (2007).
Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding.
  EMBO J, 26, 4902-4912.
PDB codes: 2qqi 2qqj 2qqk 2qql 2qqm 2qqn 2qqo
17133613 C.L.Helm, A.Zisch, and M.A.Swartz (2007).
Engineered blood and lymphatic capillaries in 3-D VEGF-fibrin-collagen matrices with interstitial flow.
  Biotechnol Bioeng, 96, 167-176.  
17626017 D.Krilleke, A.DeErkenez, W.Schubert, I.Giri, G.S.Robinson, Y.S.Ng, and D.T.Shima (2007).
Molecular mapping and functional characterization of the VEGF164 heparin-binding domain.
  J Biol Chem, 282, 28045-28056.  
17315874 N.Yamaguchi, L.Zhang, B.S.Chae, C.S.Palla, E.M.Furst, and K.L.Kiick (2007).
Growth factor mediated assembly of cell receptor-responsive hydrogels.
  J Am Chem Soc, 129, 3040-3041.  
16258170 C.J.Robinson, B.Mulloy, J.T.Gallagher, and S.E.Stringer (2006).
VEGF165-binding sites within heparan sulfate encompass two highly sulfated domains and can be liberated by K5 lyase.
  J Biol Chem, 281, 1731-1740.  
16518379 E.W.Ng, D.T.Shima, P.Calias, E.T.Cunningham, D.R.Guyer, and A.P.Adamis (2006).
Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease.
  Nat Rev Drug Discov, 5, 123-132.  
16513643 H.Jia, A.Bagherzadeh, B.Hartzoulakis, A.Jarvis, M.Löhr, S.Shaikh, R.Aqil, L.Cheng, M.Tickner, D.Esposito, R.Harris, P.C.Driscoll, D.L.Selwood, and I.C.Zachary (2006).
Characterization of a bicyclic peptide neuropilin-1 (NP-1) antagonist (EG3287) reveals importance of vascular endothelial growth factor exon 8 for NP-1 binding and role of NP-1 in KDR signaling.
  J Biol Chem, 281, 13493-13502.  
17114590 R.B.Bhisitkul (2006).
Vascular endothelial growth factor biology: clinical implications for ocular treatments.
  Br J Ophthalmol, 90, 1542-1547.  
16465447 S.Cébe-Suarez, A.Zehnder-Fjällman, and K.Ballmer-Hofer (2006).
The role of VEGF receptors in angiogenesis; complex partnerships.
  Cell Mol Life Sci, 63, 601-615.  
16787141 S.Michels, U.Schmidt-Erfurth, and P.J.Rosenfeld (2006).
Promising new treatments for neovascular age-related macular degeneration.
  Expert Opin Investig Drugs, 15, 779-793.  
16972015 Y.Yamazaki, and T.Morita (2006).
Molecular and functional diversity of vascular endothelial growth factors.
  Mol Divers, 10, 515-527.  
15693956 D.I.Holmes, and I.Zachary (2005).
The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease.
  Genome Biol, 6, 209.  
16290245 D.Ranney, P.Antich, E.Dadey, R.Mason, P.Kulkarni, O.Singh, H.Chen, A.Constantanescu, and R.Parkey (2005).
Dermatan carriers for neovascular transport targeting, deep tumor penetration and improved therapy.
  J Control Release, 109, 222-235.  
16341917 J.A.Pedersen, and M.A.Swartz (2005).
Mechanobiology in the third dimension.
  Ann Biomed Eng, 33, 1469-1490.  
16005960 M.Crombez, P.Chevallier, R.C.-Gaudreault, E.Petitclerc, D.Mantovani, and G.Laroche (2005).
Improving arterial prosthesis neo-endothelialization: application of a proactive VEGF construct onto PTFE surfaces.
  Biomaterials, 26, 7402-7409.  
16004429 N.Yamaguchi, and K.L.Kiick (2005).
Polysaccharide-poly(ethylene glycol) star copolymer as a scaffold for the production of bioactive hydrogels.
  Biomacromolecules, 6, 1921-1930.  
15902462 P.F.Dias, J.M.Siqueira, L.F.Vendruscolo, T.de Jesus Neiva, A.R.Gagliardi, M.Maraschin, and R.M.Ribeiro-do-Valle (2005).
Antiangiogenic and antitumoral properties of a polysaccharide isolated from the seaweed Sargassum stenophyllum.
  Cancer Chemother Pharmacol, 56, 436-446.  
15773911 S.P.Yang, B.O.Kwon, Y.S.Gho, and C.B.Chae (2005).
Specific interaction of VEGF165 with beta-amyloid, and its protective effect on beta-amyloid-induced neurotoxicity.
  J Neurochem, 93, 118-127.  
14570917 A.L.Goerges, and M.A.Nugent (2004).
pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.
  J Biol Chem, 279, 2307-2315.  
14689586 B.Nicholson, and D.Theodorescu (2004).
Angiogenesis and prostate cancer tumor growth.
  J Cell Biochem, 91, 125-150.  
  15215160 T.Inai, M.Mancuso, H.Hashizume, F.Baffert, A.Haskell, P.Baluk, D.D.Hu-Lowe, D.R.Shalinsky, G.Thurston, G.D.Yancopoulos, and D.M.McDonald (2004).
Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts.
  Am J Pathol, 165, 35-52.  
12811234 S.Ali, L.A.Hardy, and J.A.Kirby (2003).
Transplant immunobiology: a crucial role for heparan sulfate glycosaminoglycans?
  Transplantation, 75, 1773-1782.  
12847110 T.Merkulova-Rainon, P.England, S.Ding, C.Demerens, and G.Tobelem (2003).
The N-terminal domain of hepatocyte growth factor inhibits the angiogenic behavior of endothelial cells independently from binding to the c-met receptor.
  J Biol Chem, 278, 37400-37408.  
12359625 A.K.Ghosh, N.Hirasawa, Y.S.Lee, Y.S.Kim, K.H.Shin, N.Ryu, and K.Ohuchi (2002).
Inhibition by acharan sulphate of angiogenesis in experimental inflammation models.
  Br J Pharmacol, 137, 441-448.  
12151391 T.P.Boesen, B.Soni, T.W.Schwartz, and T.Halkier (2002).
Single-chain vascular endothelial growth factor variant with antagonist activity.
  J Biol Chem, 277, 40335-40341.  
  12485860 V.Menart, I.Fonda, M.Kenig, and V.G.Porekar (2002).
Increased in vitro cytotoxicity of TNF-alpha analog LK-805 is based on the interaction with cell surface heparan sulfate proteoglycan.
  Ann N Y Acad Sci, 973, 194-206.  
11051551 E.W.Humke, S.K.Shriver, M.A.Starovasnik, W.J.Fairbrother, and V.M.Dixit (2000).
ICEBERG: a novel inhibitor of interleukin-1beta generation.
  Cell, 103, 99.
PDB code: 1dgn
10971740 K.Norrby (2000).
2.5 kDa and 5.0 kDa heparin fragments specifically inhibit microvessel sprouting and network formation in VEGF165-mediated mammalian angiogenesis.
  Int J Exp Pathol, 81, 191-198.  
10600689 B.Olofsson, M.Jeltsch, U.Eriksson, and K.Alitalo (1999).
Current biology of VEGF-B and VEGF-C.
  Curr Opin Biotechnol, 10, 528-535.  
10562536 T.Sasaki, H.Larsson, J.Kreuger, M.Salmivirta, L.Claesson-Welsh, U.Lindahl, E.Hohenester, and R.Timpl (1999).
Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin.
  EMBO J, 18, 6240-6248.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.