8ag1: Difference between revisions
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==Crystal structure of a novel OX40 antibody== | |||
<StructureSection load='8ag1' size='340' side='right'caption='[[8ag1]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8ag1]] 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=8AG1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AG1 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.303Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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'>[https://proteopedia.org/fgij/fg.htm?mol=8ag1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ag1 OCA], [https://pdbe.org/8ag1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ag1 RCSB], [https://www.ebi.ac.uk/pdbsum/8ag1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ag1 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TNR4_HUMAN TNR4_HUMAN] Receptor for TNFSF4/OX40L/GP34. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Agonistic antibodies targeting co-stimulating receptor OX40 on T cells are considered as important as (or complementary to) the immune checkpoint blockers in cancer treatment. However, none of these agonistic antibodies have reached the late stage of clinical development partially due to the lack of intrinsic potency with the correlation between binding epitope and activity of the antibody not well understood. Here, we identified a novel anti-OX40 agonistic antibody DF004, which stimulated the proliferation of human CD4(+) T cells in vitro and inhibited tumor growth in a mouse model. Our crystallography structural studies showed that DF004 binds to the CRD2 region of OX40 while RG7888, an OX40 agonist antibody developed by Roche, binds to CRD3 of OX40 to the diametrically opposite position of DF004. This suggests that the agonistic activities of the antibodies are not necessarily epitope dependent. As their agonistic activities critically depend on clustering or cross-linking, our structural modeling indicates that the agonistic activity requires the optimal positioning of three Fc receptor/antibody/OX40 complexes on the cell membrane to facilitate the formation of one intracellular hexameric TRAF complex for downstream signal transduction, which is relatively inefficient. This may explain the lack of sufficient potency of these OX40 antibodies in a therapeutic setting and sheds light on the development of cross-linking-independent agonistic antibodies. | |||
Structural Basis of a Novel Agonistic Anti-OX40 Antibody.,Zhang J, Jiang X, Gao H, Zhang F, Zhang X, Zhou A, Xu T, Cai H Biomolecules. 2022 Aug 31;12(9):1209. doi: 10.3390/biom12091209. PMID:36139048<ref>PMID:36139048</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8ag1" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Tumor necrosis factor receptor 3D structures|Tumor necrosis factor receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Gao H]] | |||
[[Category: Zhou A]] | |||
Latest revision as of 17:20, 6 November 2024
Crystal structure of a novel OX40 antibodyCrystal structure of a novel OX40 antibody
Structural highlights
FunctionTNR4_HUMAN Receptor for TNFSF4/OX40L/GP34. Publication Abstract from PubMedAgonistic antibodies targeting co-stimulating receptor OX40 on T cells are considered as important as (or complementary to) the immune checkpoint blockers in cancer treatment. However, none of these agonistic antibodies have reached the late stage of clinical development partially due to the lack of intrinsic potency with the correlation between binding epitope and activity of the antibody not well understood. Here, we identified a novel anti-OX40 agonistic antibody DF004, which stimulated the proliferation of human CD4(+) T cells in vitro and inhibited tumor growth in a mouse model. Our crystallography structural studies showed that DF004 binds to the CRD2 region of OX40 while RG7888, an OX40 agonist antibody developed by Roche, binds to CRD3 of OX40 to the diametrically opposite position of DF004. This suggests that the agonistic activities of the antibodies are not necessarily epitope dependent. As their agonistic activities critically depend on clustering or cross-linking, our structural modeling indicates that the agonistic activity requires the optimal positioning of three Fc receptor/antibody/OX40 complexes on the cell membrane to facilitate the formation of one intracellular hexameric TRAF complex for downstream signal transduction, which is relatively inefficient. This may explain the lack of sufficient potency of these OX40 antibodies in a therapeutic setting and sheds light on the development of cross-linking-independent agonistic antibodies. Structural Basis of a Novel Agonistic Anti-OX40 Antibody.,Zhang J, Jiang X, Gao H, Zhang F, Zhang X, Zhou A, Xu T, Cai H Biomolecules. 2022 Aug 31;12(9):1209. doi: 10.3390/biom12091209. PMID:36139048[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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