| Structural highlights
Disease
[CTLA4_HUMAN] Genetic variation in CTLA4 influences susceptibility to systemic lupus erythematosus (SLE) [MIM: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.[1] Note=Genetic variations in CTLA4 may influence susceptibility to Graves disease, an autoimmune disorder associated with overactivity of the thyroid gland and hyperthyroidism.[2] Genetic variation in CTLA4 is the cause of susceptibility to diabetes mellitus insulin-dependent type 12 (IDDM12) [MIM: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.[3] [4] Genetic variation in CTLA4 is the cause of susceptibility to celiac disease type 3 (CELIAC3) [MIM: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
[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.[5] [6]
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[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chistyakov DA, Savost'anov KV, Turakulov RI, Petunina NA, Trukhina LV, Kudinova AV, Balabolkin MI, Nosikov VV. Complex association analysis of graves disease using a set of polymorphic markers. Mol Genet Metab. 2000 Jul;70(3):214-8. PMID:10924276 doi:10.1006/mgme.2000.3007
- ↑ Chistyakov DA, Savost'anov KV, Turakulov RI, Petunina NA, Trukhina LV, Kudinova AV, Balabolkin MI, Nosikov VV. Complex association analysis of graves disease using a set of polymorphic markers. Mol Genet Metab. 2000 Jul;70(3):214-8. PMID:10924276 doi:10.1006/mgme.2000.3007
- ↑ Chistyakov DA, Savost'anov KV, Turakulov RI, Petunina NA, Trukhina LV, Kudinova AV, Balabolkin MI, Nosikov VV. Complex association analysis of graves disease using a set of polymorphic markers. Mol Genet Metab. 2000 Jul;70(3):214-8. PMID:10924276 doi:10.1006/mgme.2000.3007
- ↑ Marron MP, Raffel LJ, Garchon HJ, Jacob CO, Serrano-Rios M, Martinez Larrad MT, Teng WP, Park Y, Zhang ZX, Goldstein DR, Tao YW, Beaurain G, Bach JF, Huang HS, Luo DF, Zeidler A, Rotter JI, Yang MC, Modilevsky T, Maclaren NK, She JX. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Hum Mol Genet. 1997 Aug;6(8):1275-82. PMID:9259273
- ↑ Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991 Sep 1;174(3):561-9. PMID:1714933
- ↑ Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Annu Rev Immunol. 2006;24:65-97. PMID:16551244 doi:10.1146/annurev.immunol.24.021605.090535
- ↑ 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. Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. Proc Natl Acad Sci U S A. 2017 May 8. pii: 201617941. doi:, 10.1073/pnas.1617941114. PMID:28484017 doi:http://dx.doi.org/10.1073/pnas.1617941114
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