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| | ==Crystal structure of human B7-H4 IgV-like domain== | | ==Crystal structure of human B7-H4 IgV-like domain== |
| - | <StructureSection load='4gos' size='340' side='right' caption='[[4gos]], [[Resolution|resolution]] 1.59Å' scene=''> | + | <StructureSection load='4gos' size='340' side='right'caption='[[4gos]], [[Resolution|resolution]] 1.59Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gos]] is a 1 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=4GOS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GOS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gos]] is a 1 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=4GOS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GOS 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=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 1.59Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">B7-H4, B7H4, B7S1, B7x, UNQ659/PRO1291, VTCN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=4gos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gos OCA], [http://pdbe.org/4gos PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gos RCSB], [http://www.ebi.ac.uk/pdbsum/4gos PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gos 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=4gos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gos OCA], [https://pdbe.org/4gos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gos RCSB], [https://www.ebi.ac.uk/pdbsum/4gos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gos ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/VTCN1_HUMAN VTCN1_HUMAN]] Negatively regulates T-cell-mediated immune response by inhibiting T-cell activation, proliferation, cytokine production and development of cytotoxicity. When expressed on the cell surface of tumor macrophages, plays an important role, together with regulatory T-cells (Treg), in the suppression of tumor-associated antigen-specific T-cell immunity. Involved in promoting epithelial cell transformation.<ref>PMID:15878339</ref> <ref>PMID:16606666</ref> <ref>PMID:17875732</ref> <ref>PMID:17509674</ref> [UniProtKB:Q7TSP5] | + | [https://www.uniprot.org/uniprot/VTCN1_HUMAN VTCN1_HUMAN] Negatively regulates T-cell-mediated immune response by inhibiting T-cell activation, proliferation, cytokine production and development of cytotoxicity. When expressed on the cell surface of tumor macrophages, plays an important role, together with regulatory T-cells (Treg), in the suppression of tumor-associated antigen-specific T-cell immunity. Involved in promoting epithelial cell transformation.<ref>PMID:15878339</ref> <ref>PMID:16606666</ref> <ref>PMID:17875732</ref> <ref>PMID:17509674</ref> [UniProtKB:Q7TSP5] |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | B7x (B7-H4 or B7S1) is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV) domain at 1.59 A resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7x-expressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers. |
| | + | |
| | + | Structure and cancer immunotherapy of the B7 family member B7x.,Jeon H, Vigdorovich V, Garrett-Thomson SC, Janakiram M, Ramagopal UA, Abadi YM, Lee JS, Scandiuzzi L, Ohaegbulam KC, Chinai JM, Zhao R, Yao Y, Mao Y, Sparano JA, Almo SC, Zang X Cell Rep. 2014 Nov 6;9(3):1089-98. doi: 10.1016/j.celrep.2014.09.053. Epub 2014, Oct 30. PMID:25437562<ref>PMID:25437562</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 4gos" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Almo, S C]] | + | [[Category: Large Structures]] |
| - | [[Category: Bhosle, R]] | + | [[Category: Almo SC]] |
| - | [[Category: IFN, Atoms-to-Animals:.The Immune Function Network]] | + | [[Category: Bhosle R]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Nathenson SG]] |
| - | [[Category: Nathenson, S G]] | + | [[Category: Ramagopal U]] |
| - | [[Category: Ramagopal, U]] | + | [[Category: Toro R]] |
| - | [[Category: Toro, R]] | + | [[Category: Vigdorovich V]] |
| - | [[Category: Vigdorovich, V]] | + | |
| - | [[Category: Adaptive immunity]]
| + | |
| - | [[Category: Cell surface]]
| + | |
| - | [[Category: Disulfide bond]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Immunity]]
| + | |
| - | [[Category: Immunoglobulin domain]]
| + | |
| - | [[Category: Immunoglobulin variable-like domain]]
| + | |
| - | [[Category: Nysgrc]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Psi-biology]]
| + | |
| Structural highlights
Function
VTCN1_HUMAN Negatively regulates T-cell-mediated immune response by inhibiting T-cell activation, proliferation, cytokine production and development of cytotoxicity. When expressed on the cell surface of tumor macrophages, plays an important role, together with regulatory T-cells (Treg), in the suppression of tumor-associated antigen-specific T-cell immunity. Involved in promoting epithelial cell transformation.[1] [2] [3] [4] [UniProtKB:Q7TSP5]
Publication Abstract from PubMed
B7x (B7-H4 or B7S1) is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV) domain at 1.59 A resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7x-expressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers.
Structure and cancer immunotherapy of the B7 family member B7x.,Jeon H, Vigdorovich V, Garrett-Thomson SC, Janakiram M, Ramagopal UA, Abadi YM, Lee JS, Scandiuzzi L, Ohaegbulam KC, Chinai JM, Zhao R, Yao Y, Mao Y, Sparano JA, Almo SC, Zang X Cell Rep. 2014 Nov 6;9(3):1089-98. doi: 10.1016/j.celrep.2014.09.053. Epub 2014, Oct 30. PMID:25437562[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Salceda S, Tang T, Kmet M, Munteanu A, Ghosh M, Macina R, Liu W, Pilkington G, Papkoff J. The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation. Exp Cell Res. 2005 May 15;306(1):128-41. PMID:15878339 doi:http://dx.doi.org/10.1016/j.yexcr.2005.01.018
- ↑ Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med. 2006 Apr 17;203(4):871-81. Epub 2006 Apr 10. PMID:16606666 doi:http://dx.doi.org/10.1084/jem.20050930
- ↑ Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zou W. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res. 2007 Sep 15;67(18):8900-5. PMID:17875732 doi:http://dx.doi.org/10.1158/0008-5472.CAN-07-1866
- ↑ Miyatake T, Tringler B, Liu W, Liu SH, Papkoff J, Enomoto T, Torkko KC, Dehn DL, Swisher A, Shroyer KR. B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration. Gynecol Oncol. 2007 Jul;106(1):119-27. Epub 2007 May 16. PMID:17509674 doi:http://dx.doi.org/S0090-8258(07)00198-9
- ↑ Jeon H, Vigdorovich V, Garrett-Thomson SC, Janakiram M, Ramagopal UA, Abadi YM, Lee JS, Scandiuzzi L, Ohaegbulam KC, Chinai JM, Zhao R, Yao Y, Mao Y, Sparano JA, Almo SC, Zang X. Structure and cancer immunotherapy of the B7 family member B7x. Cell Rep. 2014 Nov 6;9(3):1089-98. doi: 10.1016/j.celrep.2014.09.053. Epub 2014, Oct 30. PMID:25437562 doi:http://dx.doi.org/10.1016/j.celrep.2014.09.053
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