3p9w
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | {{STRUCTURE_3p9w| PDB=3p9w | SCENE= }} | ||
| - | ===Crystal structure of an engineered human autonomous VH Domain in complex with VEGF=== | ||
| - | {{ABSTRACT_PUBMED_23507309}} | ||
| - | ==Disease== | + | ==Crystal structure of an engineered human autonomous VH Domain in complex with VEGF== |
| + | <StructureSection load='3p9w' size='340' side='right' caption='[[3p9w]], [[Resolution|resolution]] 2.41Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[3p9w]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3P9W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3P9W FirstGlance]. <br> | ||
| + | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3b9v|3b9v]]</td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RP1-261G23.1-009, VEGF, VEGFA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3p9w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3p9w OCA], [http://pdbe.org/3p9w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3p9w RCSB], [http://www.ebi.ac.uk/pdbsum/3p9w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3p9w ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
[[http://www.uniprot.org/uniprot/VEGFA_HUMAN VEGFA_HUMAN]] Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:[http://omim.org/entry/603933 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. | [[http://www.uniprot.org/uniprot/VEGFA_HUMAN VEGFA_HUMAN]] Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:[http://omim.org/entry/603933 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 == | |
| - | ==Function== | + | |
[[http://www.uniprot.org/uniprot/VEGFA_HUMAN 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.<ref>PMID:11427521</ref> <ref>PMID:15520188</ref> <ref>PMID:16489009</ref> | [[http://www.uniprot.org/uniprot/VEGFA_HUMAN 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.<ref>PMID:11427521</ref> <ref>PMID:15520188</ref> <ref>PMID:16489009</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | We compared the capacity of an autonomous heavy chain variable (VH) domain (VH-B1a) to support diversity within its antigen-binding site relative to the conventional antigen-binding fragment (Fab) from which it was derived. We find that VH-B1a can tolerate significant diversity within all three complementarity-determining regions (CDRs) and also within framework 3, and thus, VH-B1a and the Fab are similar in terms of the regions of the antigen-binding site that can tolerate diversity without compromising stability. We constructed libraries of synthetic VH domains and isolated binders with moderate affinity for vascular endothelial growth factor (VEGF) from a library in which only CDR3 was randomized. One binder was subjected to affinity maturation to derive an autonomous VH domain (VH-V1a) that recognized both human and mouse VEGF with high affinity (KD=16nM or 10nM, respectively). Structural analysis revealed that VH-V1a binds to an epitope that is distinct from the epitopes of a natural VEGF receptor and six different anti-VEGF Fabs. Moreover, VH-V1a recognizes VEGF by using an unusual paratope consisting predominantly of CDR3 but with significant contributions from framework residues within the former light chain interface. These results suggest that VH-B1a and other autonomous VH domains may be useful scaffolds to support both conventional libraries with antigen-binding sites built from the three CDR loops and, also, nonconventional libraries with antigen-binding sites built from CDR3 and the former light chain interface. | ||
| + | |||
| + | Design of Synthetic Autonomous V Domain Libraries and Structural Analysis of a V Domain Bound to Vascular Endothelial Growth Factor.,Ma X, Barthelemy PA, Rouge L, Wiesmann C, Sidhu SS J Mol Biol. 2013 Mar 16. pii: S0022-2836(13)00168-X. doi:, 10.1016/j.jmb.2013.03.020. PMID:23507309<ref>PMID:23507309</ref> | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 3p9w" style="background-color:#fffaf0;"></div> | ||
| - | == | + | ==See Also== |
| - | + | *[[Vascular Endothelial Growth Factor|Vascular Endothelial Growth Factor]] | |
| - | [[Category: | + | == References == |
| - | [[Category: Ma, X | + | <references/> |
| - | [[Category: Wiesmann, C | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Human]] | ||
| + | [[Category: Ma, X]] | ||
| + | [[Category: Wiesmann, C]] | ||
[[Category: Cystine knot cytokine]] | [[Category: Cystine knot cytokine]] | ||
[[Category: Signaling protein]] | [[Category: Signaling protein]] | ||
Revision as of 05:31, 5 August 2016
Crystal structure of an engineered human autonomous VH Domain in complex with VEGF
| |||||||||||
