5tru

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== Function ==
== Function ==
[[http://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>
[[http://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 ==
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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.
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
== References ==
<references/>
<references/>

Revision as of 07:04, 24 May 2017

Structure of the first-in-class checkpoint inhibitor Ipilimumab bound to human CTLA-4

5tru, resolution 3.00Å

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