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PDBsum entry 1vpp
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protein Protein-protein interface(s) links
Growth factor/growth factor inhibitor PDB id
1vpp

 

 

 

 

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Contents
Protein chains
96 a.a. *
90 a.a. *
20 a.a. *
18 a.a. *
Waters ×383
* Residue conservation analysis
PDB id:
1vpp
Name: Growth factor/growth factor inhibitor
Title: Complex between vegf and a receptor blocking peptide
Structure: Protein (vascular endothelial growth factor). Chain: v, w. Fragment: receptor binding domain. Synonym: vegf, vascular permeability factor, vpf. Engineered: yes. Protein (peptide v108). Chain: x, y. Fragment: receptor blocking peptide. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this sequence is chemically synthesized
Biol. unit: Tetramer (from PQS)
Resolution:
1.90Å     R-factor:   0.190     R-free:   0.270
Authors: C.Wiesmann,H.W.Christinger,A.G.Cochran,B.C.Cunningham, W.J.Fairbrother,C.J.Keenan,G.Meng,A.M.De Vos
Key ref:
C.Wiesmann et al. (1998). Crystal structure of the complex between VEGF and a receptor-blocking peptide. Biochemistry, 37, 17765-17772. PubMed id: 9922142 DOI: 10.1021/bi9819327
Date:
09-Oct-98     Release date:   23-Feb-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P15692  (VEGFA_HUMAN) -  Vascular endothelial growth factor A, long form from Homo sapiens
Seq:
Struc: 		395 a.a.
96 a.a.
Protein chain
Pfam   ArchSchema ?
P15692  (VEGFA_HUMAN) -  Vascular endothelial growth factor A, long form from Homo sapiens
Seq:
Struc: 		395 a.a.
90 a.a.
Protein chain
No UniProt id for this chain
Struc: 20 a.a.
Protein chain
No UniProt id for this chain
Struc: 18 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1021/bi9819327 Biochemistry 37:17765-17772 (1998)
PubMed id: 9922142  
 
 
Crystal structure of the complex between VEGF and a receptor-blocking peptide.
C.Wiesmann, H.W.Christinger, A.G.Cochran, B.C.Cunningham, W.J.Fairbrother, C.J.Keenan, G.Meng, A.M.de Vos.
 
  ABSTRACT  
 
Vascular endothelial growth factor (VEGF) is a specific and potent angiogenic factor and, therefore, a prime therapeutic target for the development of antagonists for the treatment of cancer. As a first step toward this goal, phage display was used to generate peptides that bind to the receptor-binding domain (residues 8-109) of VEGF and compete with receptor [Fairbrother, W. J., Christinger, H. W., Cochran, A. G., Fuh, G., Keenan, C. J., Quan, C., Shriver, S. K., Tom, J. Y. K., Wells, J. A., and Cunningham, B. C. (1999) Biochemistry 38, 17754-17764]. The crystal structure of VEGF in complex with one of these peptides was solved and refined to a resolution of 1.9 A. The 20-mer peptide is unstructured in solution and adopts a largely extended conformation when bound to VEGF. Residues 3-8 form a beta-strand which pairs with strand beta6 of VEGF via six hydrogen bonds. The C-terminal four residues of the peptide point away from the growth factor, consistent with NMR data indicating that these residues are flexible in the complex in solution. In contrast, shortening the N-terminus of the peptide leads to decreased binding affinities. Truncation studies show that the peptide can be reduced to 14 residues with only moderate effect on binding affinity. However, because of the extended conformation and the scarcity of specific side-chain interactions with VEGF, the peptide is not a promising lead for small-molecule development. The interface between the peptide and VEGF contains a subset of the residues recognized by a neutralizing Fab fragment and overlaps partially with the binding site for the Flt-1 receptor. The location of the peptide-binding site and the hydrophilic character of the interactions with VEGF resemble more the binding mode of the Fab fragment than that of the receptor.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20890540 L.Li, B.P.Orner, T.Huang, A.P.Hinck, and L.L.Kiessling (2010).
Peptide ligands that use a novel binding site to target both TGF-β receptors.
  Mol Biosyst, 6, 2392-2402.  
19025993 A.S.Potty, K.Kourentzi, H.Fang, G.W.Jackson, X.Zhang, G.B.Legge, and R.C.Willson (2009).
Biophysical characterization of DNA aptamer interactions with vascular endothelial growth factor.
  Biopolymers, 91, 145-156.  
18440319 E.Vivès, J.Schmidt, and A.Pèlegrin (2008).
Cell-penetrating and cell-targeting peptides in drug delivery.
  Biochim Biophys Acta, 1786, 126-138.  
18485899 J.H.Lee, F.Jucker, and A.Pardi (2008).
Imino proton exchange rates imply an induced-fit binding mechanism for the VEGF165-targeting aptamer, Macugen.
  FEBS Lett, 582, 1835-1839.  
16373345 G.Fuh, P.Wu, W.C.Liang, M.Ultsch, C.V.Lee, B.Moffat, and C.Wiesmann (2006).
Structure-function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab.
  J Biol Chem, 281, 6625-6631.
PDB codes: 2fjf 2fjg 2fjh
16492159 L.D.D'Andrea, A.Del Gatto, C.Pedone, and E.Benedetti (2006).
Peptide-based molecules in angiogenesis.
  Chem Biol Drug Des, 67, 115-126.  
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.  
16186493 L.D.D'Andrea, G.Iaccarino, R.Fattorusso, D.Sorriento, C.Carannante, D.Capasso, B.Trimarco, and C.Pedone (2005).
Targeting angiogenesis: structural characterization and biological properties of a de novo engineered VEGF mimicking peptide.
  Proc Natl Acad Sci U S A, 102, 14215-14220.  
15911380 L.Gardiner, B.J.Coyle, W.C.Chan, and P.Soultanas (2005).
Discovery of antagonist peptides against bacterial helicase-primase interaction in B. stearothermophilus by reverse yeast three-hybrid.
  Chem Biol, 12, 595-604.  
14522049 A.C.Anderson (2003).
The process of structure-based drug design.
  Chem Biol, 10, 787-797.  
12551914 A.Kiba, N.Yabana, and M.Shibuya (2003).
A set of loop-1 and -3 structures in the novel vascular endothelial growth factor (VEGF) family member, VEGF-ENZ-7, is essential for the activation of VEGFR-2 signaling.
  J Biol Chem, 278, 13453-13461.  
12512072 S.S.Sidhu, W.J.Fairbrother, and K.Deshayes (2003).
Exploring protein-protein interactions with phage display.
  Chembiochem, 4, 14-25.  
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.  
12207021 Y.A.Muller, C.Heiring, R.Misselwitz, K.Welfle, and H.Welfle (2002).
The cystine knot promotes folding and not thermodynamic stability in vascular endothelial growth factor.
  J Biol Chem, 277, 43410-43416.
PDB codes: 1mjv 1mkg 1mkk
11445463 D.J.Christensen, E.B.Gottlin, R.E.Benson, and P.T.Hamilton (2001).
Phage display for target-based antibacterial drug discovery.
  Drug Discov Today, 6, 721-727.  
10779412 A.G.Cochran (2000).
Antagonists of protein-protein interactions.
  Chem Biol, 7, R85-R94.  
10753817 M.C.Deller, and E.Yvonne Jones (2000).
Cell surface receptors.
  Curr Opin Struct Biol, 10, 213-219.  
10449375 R.W.Roberts, and W.W.Ja (1999).
In vitro selection of nucleic acids and proteins: What are we learning?
  Curr Opin Struct Biol, 9, 521-529.  
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.

 

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