+ Most Popular
Cunninghamia lanceolata plantations in China
Mammalian lairs in paleo ecological studies and palynology
Studies on technological possibilities in utilization of anhydrous milk fat for production of recombined butter-like products
Should right-sided fibroelastomas be operated upon?
Large esophageal lipoma
Apoptosis in the mammalian thymus during normal histogenesis and under various in vitro and in vivo experimental conditions
Poissons characoides nouveaux ou non signales de l'Ilha do Bananal, Bresil
Desensitizing efficacy of Colgate Sensitive Maximum Strength and Fresh Mint Sensodyne dentifrices
Administration of fluid by subcutaneous infusion: revival of a forgotten method
Tundra mosquito control - an impossible dream?
Schizophrenia for primary care providers: how to contribute to the care of a vulnerable patient population
Geochemical pattern analysis; method of describing the Southeastern limestone regional aquifer system
Incidence of low birth weights in a hospital of Mexico City
Graded management intensity of grassland systems for enhancing floristic diversity
Microbiology and biochemistry of cheese and fermented milk
The ember tetra: a new pygmy characid tetra from the Rio das Mortes, Brazil, Hyphessobrycon amandae sp. n. (Pisces, Characoidei)
Risk factors of contrast-induced nephropathy in patients after coronary artery intervention
Renovation of onsite domestic wastewater in a poorly drained soil
Observations of the propagation velocity and formation mechanism of burst fractures caused by gunshot
Systolic blood pressure in a population of infants in the first year of life: the Brompton study
Haematological studies in rats fed with metanil yellow
Studies on pasteurellosis. I. A new species of Pasteurella encountered in chronic fowl cholera
Dormancy breaking and germination of Acacia salicina Lindl. seeds
therapy of lupus nephritis. a two-year prospective study

Crystal structure of the complex between VEGF and a receptor-blocking peptide

Crystal structure of the complex between VEGF and a receptor-blocking peptide

Biochemistry 37(51): 17765-17772

ISSN/ISBN: 0006-2960

PMID: 9922142

DOI: 10.1021/bi9819327

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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 045677754

Download citation: RISBibTeXText

Related references

Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91(5): 695-704, 1997

Viral escape at the molecular level explained by quantitative T-cell receptor/peptide/MHC interactions and the crystal structure of a peptide/MHC complex. Journal of Molecular Biology 302(4): 873-885, 2000

Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: implications for peptide binding and T-cell receptor recognition. Proceedings of the National Academy of Sciences of the United States of America 89(17): 8403-8407, 1992

The crystal structure of a T cell receptor in complex with peptide and MHC class II. Science 286(5446): 1913-1921, 1999

Crystal structure of the plant receptor-like kinase TDR in complex with the TDIF peptide. Nature Communications 7: 12383, 2016

Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4. Proceedings of the National Academy of Sciences of the United States of America 109(14): 5405-5410, 2012

Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor. Journal of Biological Chemistry 285(1): 723-730, 2010

Structure of a VEGF-VEGF receptor complex determined by electron microscopy. Nature Structural and Molecular Biology 14(3): 249-250, 2007

Crystal structure of human endothelin ET B receptor in complex with peptide inverse agonist IRL2500. Communications Biology 2(1): 236, 2019

Crystal structure of human endothelin ET B receptor in complex with peptide inverse agonist IRL2500. Communications Biology 2: 236, 2019

High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist. Nature Structural and Molecular Biology 25(12): 1086-1092, 2018

Crystal structure of PXY-TDIF complex reveals a conserved recognition mechanism among CLE peptide-receptor pairs. Cell Research 26(5): 543-555, 2016

Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. Embo Journal 16(18): 5572-5581, 1997

A major histocompatibility complex-peptide-restricted antibody and t cell receptor molecules recognize their target by distinct binding modes: crystal structure of human leukocyte antigen (HLA)-A1-MAGE-A1 in complex with FAB-HYB3. Journal of Biological Chemistry 280(4): 2972-2980, 2005

A fusion protein with the receptor-binding domain of vascular endothelial growth factor-A (VEGF-A) is an antagonist of angiogenesis in cancer treatment: Simultaneous blocking of VEGF receptor-1 and 2. Cancer Biology and Therapy 10(9): 865-873, 2010