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1cz8

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[[Image:1cz8.png|left|200px]]
 
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==VASCULAR ENDOTHELIAL GROWTH FACTOR IN COMPLEX WITH AN AFFINITY MATURED ANTIBODY==
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The line below this paragraph, containing "STRUCTURE_1cz8", creates the "Structure Box" on the page.
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<StructureSection load='1cz8' size='340' side='right'caption='[[1cz8]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[1cz8]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CZ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1CZ8 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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{{STRUCTURE_1cz8| PDB=1cz8 | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1cz8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1cz8 OCA], [https://pdbe.org/1cz8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1cz8 RCSB], [https://www.ebi.ac.uk/pdbsum/1cz8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1cz8 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://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:[https://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.
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== Function ==
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[https://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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cz/1cz8_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1cz8 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The Fab portion of a humanized antibody (Fab-12; IgG form known as rhuMAb VEGF) to vascular endothelial growth factor (VEGF) has been affinity-matured through complementarity-determining region (CDR) mutation, followed by affinity selection using monovalent phage display. After stringent binding selections at 37 degrees C, with dissociation (off-rate) selection periods of several days, high affinity variants were isolated from CDR-H1, H2, and H3 libraries. Mutations were combined to obtain cumulatively tighter-binding variants. The final variant identified here, Y0317, contained six mutations from the parental antibody. In vitro cell-based assays show that four mutations yielded an improvement of about 100-fold in potency for inhibition of VEGF-dependent cell proliferation by this variant, consistent with the equilibrium binding constant determined from kinetics experiments at 37 degrees C. Using X-ray crystallography, we determined a high-resolution structure of the complex between VEGF and the affinity-matured Fab fragment. The overall features of the binding interface seen previously with wild-type are preserved, and many contact residues are maintained in precise alignment in the superimposed structures. However, locally, we see evidence for improved contacts between antibody and antigen, and two mutations result in increased van der Waals contact and improved hydrogen bonding. Site-directed mutants confirm that the most favorable improvements as judged by examination of the complex structure, in fact, have the greatest impact on free energy of binding. In general, the final antibody has improved affinity for several VEGF variants as compared with the parental antibody; however, some contact residues on VEGF differ in their contribution to the energetics of Fab binding. The results show that small changes even in a large protein-protein binding interface can have significant effects on the energetics of interaction.
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===VASCULAR ENDOTHELIAL GROWTH FACTOR IN COMPLEX WITH AN AFFINITY MATURED ANTIBODY===
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Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen.,Chen Y, Wiesmann C, Fuh G, Li B, Christinger HW, McKay P, de Vos AM, Lowman HB J Mol Biol. 1999 Nov 5;293(4):865-81. PMID:10543973<ref>PMID:10543973</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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The line below this paragraph, {{ABSTRACT_PUBMED_10543973}}, adds the Publication Abstract to the page
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<div class="pdbe-citations 1cz8" style="background-color:#fffaf0;"></div>
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(as it appears on PubMed at http://www.pubmed.gov), where 10543973 is the PubMed ID number.
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{{ABSTRACT_PUBMED_10543973}}
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==About this Structure==
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[[1cz8]] is a 6 chain structure of [[Vascular Endothelial Growth Factor]] with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CZ8 OCA].
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==See Also==
==See Also==
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*[[Vascular Endothelial Growth Factor|Vascular Endothelial Growth Factor]]
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*[[Antibody 3D structures|Antibody 3D structures]]
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*[[VEGF 3D Structures|VEGF 3D Structures]]
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==Reference==
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*[[3D structures of human antibody|3D structures of human antibody]]
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<ref group="xtra">PMID:010543973</ref><references group="xtra"/>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
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[[Category: Chen, Y.]]
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[[Category: Chen Y]]
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[[Category: Christinger, H W.]]
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[[Category: Christinger HW]]
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[[Category: Fuh, G.]]
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[[Category: Fuh G]]
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[[Category: Li, B.]]
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[[Category: Li B]]
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[[Category: Lowman, H B.]]
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[[Category: Lowman HB]]
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[[Category: McKay, P.]]
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[[Category: McKay P]]
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[[Category: Vos, A M.de.]]
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[[Category: Wiesmann C]]
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[[Category: Wiesmann, C.]]
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[[Category: De Vos AM]]
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[[Category: Cystine knot]]
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[[Category: Fab fragment]]
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[[Category: Immune system]]
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Current revision

VASCULAR ENDOTHELIAL GROWTH FACTOR IN COMPLEX WITH AN AFFINITY MATURED ANTIBODY

PDB ID 1cz8

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