4wpb

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Revision as of 18:49, 1 February 2017

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

Structural highlights

4wpb is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:	, , , , ,
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

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 alpha- and beta-amino acid residues ("alpha/beta-peptides") that mimic several peptides derived from the three-helix bundle "Z-domain" scaffold. We show that alpha/beta-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 alpha/beta-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 alpha/beta-peptides that bind to two other protein partners, IgG and tumor necrosis factor-alpha. 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 alpha/beta-peptides that bind tightly and specifically to diverse targets of biomedical interest. Such reagents would be useful for diagnostic and therapeutic applications.

Targeting diverse protein-protein interaction interfaces with alpha/beta-peptides derived from the Z-domain scaffold.,Checco JW, Kreitler DF, Thomas NC, Belair DG, Rettko NJ, Murphy WL, Forest KT, Gellman SH Proc Natl Acad Sci U S A. 2015 Mar 30. pii: 201420380. PMID:25825775^[4]

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

References

↑ 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
↑ 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
↑ 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
↑ Checco JW, Kreitler DF, Thomas NC, Belair DG, Rettko NJ, Murphy WL, Forest KT, Gellman SH. Targeting diverse protein-protein interaction interfaces with alpha/beta-peptides derived from the Z-domain scaffold. Proc Natl Acad Sci U S A. 2015 Mar 30. pii: 201420380. PMID:25825775 doi:http://dx.doi.org/10.1073/pnas.1420380112

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4wpb"

@@ Line 1: / Line 1: @@
 ==Vascular endothelial growth factor in complex with alpha/beta-VEGF-1==
 <StructureSection load='4wpb' size='340' side='right' caption='[[4wpb]], [[Resolution|resolution]] 3.11&Aring;' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[4wpb]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WPB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WPB FirstGlance]. <br>
 </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=3FB:(3S)-3-AMINO-4-PHENYLBUTANOIC+ACID'>3FB</scene>, <scene name='pdbligand=AIB:ALPHA-AMINOISOBUTYRIC+ACID'>AIB</scene>, <scene name='pdbligand=B3D:3-AMINOPENTANEDIOIC+ACID'>B3D</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=XCP:(1S,2S)-2-AMINOCYCLOPENTANECARBOXYLIC+ACID'>XCP</scene>, <scene name='pdbligand=XPC:(3S,4R)-4-AMINOPYRROLIDINE-3-CARBOXYLIC+ACID'>XPC</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wpb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4wpb RCSB], [http://www.ebi.ac.uk/pdbsum/4wpb PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wpb OCA], [http://pdbe.org/4wpb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wpb RCSB], [http://www.ebi.ac.uk/pdbsum/4wpb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wpb ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4wpb" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4wpb

From Proteopedia

Revision as of 18:49, 1 February 2017

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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