View source for 9dq4


==Crystal structure of engineered Ipilimumab (mipi.4) Fab in complex with mouse CTLA-4==
<StructureSection load='9dq4' size='340' side='right'caption='[[9dq4]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9dq4]] is a 3 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=9DQ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DQ4 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]] 1.57&#8491;</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=FUC:ALPHA-L-FUCOSE'>FUC</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'>[https://proteopedia.org/fgij/fg.htm?mol=9dq4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9dq4 OCA], [https://pdbe.org/9dq4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9dq4 RCSB], [https://www.ebi.ac.uk/pdbsum/9dq4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9dq4 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CTLA4_MOUSE CTLA4_MOUSE] Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28 (By similarity).
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== Publication Abstract from PubMed ==
Testing of candidate monoclonal antibody therapeutics in preclinical models is an essential step in drug development. Identification of antibody therapeutic candidates that bind their human targets and cross-react to mouse orthologs is often challenging, especially for targets with low sequence homology. In such cases, surrogate antibodies that bind mouse orthologs must be used. The antibody 9D9, which binds mouse CTLA-4, is a commonly used surrogate for CTLA-4 checkpoint blockade studies in mouse cancer models. In this work, we reveal that 9D9 has significant biophysical dissimilarities to therapeutic CTLA-4 antibodies. The 9D9-mCTLA4 complex crystal structure was determined and shows that the surrogate antibody binds an epitope distinct from ipilimumab and tremelimumab. In addition, while ipilimumab has pH-independent binding to hCTLA-4, 9D9 loses binding to mCTLA-4 at physiologically relevant acidic pH ranges. We used phage and yeast display to engineer ipilimumab to bind mouse CTLA-4 with single-digit nM affinity from an initial state with no apparent binding. The engineered variants showed pH-independent and cross-reactive binding to both mouse and human CTLA-4. Crystal structures of a variant in complex with both mouse and human CTLA-4 confirmed that it targets an equivalent epitope as ipilimumab. These cross-reactive ipilimumab variants may facilitate improved translatability and future mechanism-of-action studies for anti-CTLA-4 targeting in murine models.

Engineered ipilimumab variants that bind human and mouse CTLA-4.,Robison B, Diong SJ, Kumar A, Moon TM, Chang O, Chau B, Bee C, Barman I, Rajpal A, Korman AJ, West S, Strop P, Lee PS MAbs. 2025 Dec;17(1):2451296. doi: 10.1080/19420862.2025.2451296. Epub 2025 Jan , 24. PMID:39849917<ref>PMID:39849917</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9dq4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Diong SJ]]
[[Category: Lee PS]]