5o4e

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of VEGF in complex with heterodimeric Fcab JanusCT6

Structural highlights

5o4e is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.15Å
Ligands:	, , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IGG1_HUMAN Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).^[1] ^[2] ^[3]

Publication Abstract from PubMed

Fcabs (Fc domain with antigen-binding sites) are promising novel therapeutics. By engineering of the C-terminal loops of the CH3 domains, two antigen binding sites can be inserted in close proximity. In order to elucidate the binding mode(s) between homodimeric Fcabs and small homodimeric antigens, the interaction between the Fcabs 448 and CT6 (having the AB, CD and EF loops and the C-termini engineered) with homodimeric VEGF was investigated. The crystal structures of these Fcabs, which form polymers with the antigen VEGF in solution, were determined. However, construction of heterodimeric Fcabs (JanusFcabs: one chain Fc-wt, one chain VEGF-binding) results in formation of distinct JanusFcab-VEGF complexes (2:1), which allowed elucidation of the crystal structure of the JanusCT6-VEGF complex at 2.15 A resolution. VEGF binding to Janus448 and JanusCT6 is shown to be entropically unfavorable, but enthalpically favorable. Structure-function relationships are discussed with respect to Fcab design and engineering strategies.

Two-Faced Fcab Prevents Polymerization with VEGF and Reveals Thermodynamics and the 2.15 A Crystal Structure of the Complex.,Lobner E, Humm AS, Mlynek G, Kubinger K, Kitzmuller M, Traxlmayr MW, Djinovic-Carugo K, Obinger C MAbs. 2017 Aug 17:0. doi: 10.1080/19420862.2017.1364825. PMID:28816592^[4]

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

References

↑ Teng G, Papavasiliou FN. Immunoglobulin somatic hypermutation. Annu Rev Genet. 2007;41:107-20. PMID:17576170 doi:http://dx.doi.org/10.1146/annurev.genet.41.110306.130340
↑ Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S41-52. doi:, 10.1016/j.jaci.2009.09.046. PMID:20176268 doi:http://dx.doi.org/10.1016/j.jaci.2009.09.046
↑ McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol. 2011 Dec 9;12(1):24-34. doi: 10.1038/nri3128. PMID:22158414 doi:http://dx.doi.org/10.1038/nri3128
↑ Lobner E, Humm AS, Mlynek G, Kubinger K, Kitzmuller M, Traxlmayr MW, Djinovic-Carugo K, Obinger C. Two-Faced Fcab Prevents Polymerization with VEGF and Reveals Thermodynamics and the 2.15 A Crystal Structure of the Complex. MAbs. 2017 Aug 17:0. doi: 10.1080/19420862.2017.1364825. PMID:28816592 doi:http://dx.doi.org/10.1080/19420862.2017.1364825

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5o4e"

@@ Line 1: / Line 1: @@
 ==Crystal structure of VEGF in complex with heterodimeric Fcab JanusCT6==
-<StructureSection load='5o4e' size='340' side='right' caption='[[5o4e]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
+<StructureSection load='5o4e' size='340' side='right'caption='[[5o4e]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5o4e]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O4E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5O4E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5o4e]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5O4E FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5k64|5k64]], [[5k65|5k65]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=5o4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o4e OCA], [http://pdbe.org/5o4e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5o4e RCSB], [http://www.ebi.ac.uk/pdbsum/5o4e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5o4e ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5o4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o4e OCA], [https://pdbe.org/5o4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5o4e RCSB], [https://www.ebi.ac.uk/pdbsum/5o4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5o4e 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.
 == 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/IGG1_HUMAN IGG1_HUMAN]] Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).<ref>PMID:17576170</ref> <ref>PMID:20176268</ref> <ref>PMID:22158414</ref>
+[https://www.uniprot.org/uniprot/IGG1_HUMAN IGG1_HUMAN] Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).<ref>PMID:17576170</ref> <ref>PMID:20176268</ref> <ref>PMID:22158414</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 19: @@
 </div>
 <div class="pdbe-citations 5o4e" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[VEGF 3D Structures|VEGF 3D Structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Djinovic-Carugo, K]]
+[[Category: Homo sapiens]]
-[[Category: Humm, A]]
+[[Category: Large Structures]]
-[[Category: Kubinger, K]]
+[[Category: Djinovic-Carugo K]]
-[[Category: Lobner, E]]
+[[Category: Humm A]]
-[[Category: Mlynek, G]]
+[[Category: Kubinger K]]
-[[Category: Obinger, C]]
+[[Category: Lobner E]]
-[[Category: Antibody engineering]]
+[[Category: Mlynek G]]
-[[Category: Ch3 domain]]
+[[Category: Obinger C]]
-[[Category: Fc fragment]]
-[[Category: Fcab]]
-[[Category: Heterodimeric fcab]]
-[[Category: Immune system]]
-[[Category: Immunoglobulin g1]]
-[[Category: Vascular endothelial growth factor]]
-[[Category: Vegf]]

5o4e

From Proteopedia

Current revision

Crystal structure of VEGF in complex with heterodimeric Fcab JanusCT6

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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