| 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
Monoclonal antibody based immune checkpoint blockade therapies have achieved clinical successes in management of malignant tumors. As the first monoclonal antibody targeting immune checkpoint molecules entered into clinics, the molecular basis of ipilimumab-based anti-CTLA-4 blockade has not yet been fully understood. In the present study, we report the complex structure of ipilimumab and CTLA-4. The complex structure showed similar contributions from VH and VL of ipilimumab in binding to CTLA-4 front beta-sheet strands. The blockade mechanism of ipilimumab is that the strands of CTLA-4 contributing to the binding to B7-1 or B7-2 were occupied by ipilimumab and thereafter prevents the binding of B7-1 or B7-2 to CTLA-4. Though ipilimumab binds to the same epitope with tremelimumab on CTLA-4 with similar binding affinity, the higher dissociation rate of ipilimumab may indicate the dynamic binding to CTLA-4, which may affect its pharmacokinetics. The molecular basis of ipilimumab-based anti-CTLA-4 blockade and comparative study of the binding characteristics of ipilimumab and tremelimumab would shed light for the discovery of small molecular inhibitors and structure-based monoclonal antibody optimization or new biologics.
Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies.,He M, Chai Y, Qi J, Zhang CWH, Tong Z, Shi Y, Yan J, Tan S, Gao GF Oncotarget. 2017 May 19;8(40):67129-67139. doi: 10.18632/oncotarget.18004., eCollection 2017 Sep 15. PMID:28978021[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
- ↑ He M, Chai Y, Qi J, Zhang CWH, Tong Z, Shi Y, Yan J, Tan S, Gao GF. Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies. Oncotarget. 2017 May 19;8(40):67129-67139. doi: 10.18632/oncotarget.18004., eCollection 2017 Sep 15. PMID:28978021 doi:http://dx.doi.org/10.18632/oncotarget.18004
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