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==Structure of the first-in-class checkpoint inhibitor Ipilimumab bound to human CTLA-4==
<StructureSection load='5tru' size='340' side='right'caption='[[5tru]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5tru]] 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=5TRU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TRU 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&#8491;</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=5tru FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tru OCA], [https://pdbe.org/5tru PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tru RCSB], [https://www.ebi.ac.uk/pdbsum/5tru PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tru 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> 
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== Publication Abstract from PubMed ==
Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 A resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front beta-sheet of CTLA-4 and intersects with the CTLA-4:Beta7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab.,Ramagopal UA, Liu W, Garrett-Thomson SC, Bonanno JB, Yan Q, Srinivasan M, Wong SC, Bell A, Mankikar S, Rangan VS, Deshpande S, Korman AJ, Almo SC Proc Natl Acad Sci U S A. 2017 May 8. pii: 201617941. doi:, 10.1073/pnas.1617941114. PMID:28484017<ref>PMID:28484017</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 5tru" style="background-color:#fffaf0;"></div>

==See Also==
*[[CTLA-4|CTLA-4]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Almo SC]]
[[Category: Bell A]]
[[Category: Bonanno JB]]
[[Category: Deshpande S]]
[[Category: Garrett-Thomson SC]]
[[Category: Korman AJ]]
[[Category: Liu W]]
[[Category: Mankikar S]]
[[Category: Ramagopal UA]]
[[Category: Rangan VS]]
[[Category: Srinivasan M]]
[[Category: Wong SC]]
[[Category: Yan Q]]