4WPB

Vascular endothelial growth factor in complex with alpha/beta-VEGF-1

Summary for 4WPB

• Entry DOI: 10.2210/pdb4wpb/pdb
• Descriptor: Vascular endothelial growth factor A, alpha/beta-VEGF-1 (2 entities in total)
• Functional Keywords: alpha/beta-peptide, foldamer, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 33083.86

Authors

Kreitler, D.F.,Checco, J.W.,Gellman, S.H.,Forest, K.T. (deposition date: 2014-10-17, release date: 2015-04-15, Last modification date: 2024-07-10)

Primary citation

Checco, J.W.,Kreitler, D.F.,Thomas, N.C.,Belair, D.G.,Rettko, N.J.,Murphy, W.L.,Forest, K.T.,Gellman, S.H.
Targeting diverse protein-protein interaction interfaces with alpha / beta-peptides derived from the Z-domain scaffold.
Proc.Natl.Acad.Sci.USA, 112:4552-4557, 2015

PubMed Abstract: Peptide-based agents derived from well-defined scaffolds offer an alternative to antibodies for selective and high-affinity recognition of large and topologically complex protein surfaces. Here, we describe a strategy for designing oligomers containing both α- and β-amino acid residues ("α/β-peptides") that mimic several peptides derived from the three-helix bundle "Z-domain" scaffold. We show that α/β-peptides derived from a Z-domain peptide targeting vascular endothelial growth factor (VEGF) can structurally and functionally mimic the binding surface of the parent peptide while exhibiting significantly decreased susceptibility to proteolysis. The tightest VEGF-binding α/β-peptide inhibits the VEGF165-induced proliferation of human umbilical vein endothelial cells. We demonstrate the versatility of this strategy by showing how principles underlying VEGF signaling inhibitors can be rapidly extended to produce Z-domain-mimetic α/β-peptides that bind to two other protein partners, IgG and tumor necrosis factor-α. Because well-established selection techniques can identify high-affinity Z-domain derivatives from large DNA-encoded libraries, our findings should enable the design of biostable α/β-peptides that bind tightly and specifically to diverse targets of biomedical interest. Such reagents would be useful for diagnostic and therapeutic applications.

PubMed: 25825775
DOI: 10.1073/pnas.1420380112

Experimental method

X-RAY DIFFRACTION (3.11 Å)