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==Crystal structure of an acidic pH-selective Ipilimumab variant Ipi.106 in complex with CTLA-4==
<StructureSection load='7su1' size='340' side='right'caption='[[7su1]], [[Resolution|resolution]] 2.53&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7su1]] 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=7SU1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SU1 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]] 2.53&#8491;</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>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</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=7su1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7su1 OCA], [https://pdbe.org/7su1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7su1 RCSB], [https://www.ebi.ac.uk/pdbsum/7su1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7su1 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CTLA4_HUMAN CTLA4_HUMAN] Genetic variation in CTLA4 influences susceptibility to systemic lupus erythematosus (SLE) [MIM:[https://omim.org/entry/152700 152700]. SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. SLE is thought to represent a failure of the regulatory mechanisms of the autoimmune system.<ref>PMID:10924276</ref>   Note=Genetic variations in CTLA4 may influence susceptibility to Graves disease, an autoimmune disorder associated with overactivity of the thyroid gland and hyperthyroidism.<ref>PMID:10924276</ref>   Genetic variation in CTLA4 is the cause of susceptibility to diabetes mellitus insulin-dependent type 12 (IDDM12) [MIM:[https://omim.org/entry/601388 601388]. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:10924276</ref> <ref>PMID:9259273</ref>   Genetic variation in CTLA4 is the cause of susceptibility to celiac disease type 3 (CELIAC3) [MIM:[https://omim.org/entry/609755 609755]. It is a multifactorial disorder of the small intestine that is influenced by both environmental and genetic factors. It is characterized by malabsorption resulting from inflammatory injury to the mucosa of the small intestine after the ingestion of wheat gluten or related rye and barley proteins. In its classic form, celiac disease is characterized in children by malabsorption and failure to thrive.
== Function ==
[https://www.uniprot.org/uniprot/CTLA4_HUMAN CTLA4_HUMAN] 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.<ref>PMID:1714933</ref> <ref>PMID:16551244</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that prevents maximal efficacious clinical outcomes and can lead to discontinuation of treatment. We hypothesized that an acidic pH-selective ipilimumab (pH Ipi), which preferentially and reversibly targets the acidic tumor microenvironment over the neutral periphery, may have a more favorable therapeutic index. While ipilimumab has pH-independent CTLA-4 affinity, pH Ipi variants have been engineered to have up to 50-fold enhanced affinity to CTLA-4 at pH 6.0 compared to pH 7.4. In hCTLA-4 knock-in mice, these variants have maintained anti-tumor activity and reduced peripheral activation, a surrogate marker for toxicity. pH-sensitive therapeutic antibodies may be a differentiating paradigm and a novel modality for enhanced tumor targeting and improved safety profiles.

Improved therapeutic index of an acidic pH-selective antibody.,Lee PS, MacDonald KG, Massi E, Chew PV, Bee C, Perkins P, Chau B, Thudium K, Lohre J, Nandi P, Deyanova EG, Barman I, Gudmundsson O, Dollinger G, Sproul T, Engelhardt JJ, Strop P, Rajpal A MAbs. 2022 Jan-Dec;14(1):2024642. doi: 10.1080/19420862.2021.2024642. PMID:35192429<ref>PMID:35192429</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7su1" style="background-color:#fffaf0;"></div>

==See Also==
*[[Antibody 3D structures|Antibody 3D structures]]
*[[CTLA-4|CTLA-4]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chau B]]
[[Category: Lee PS]]
[[Category: Strop P]]