7su0

From Proteopedia

(Difference between revisions)

Revision as of 16:54, 18 October 2023

Crystal structure of an acidic pH-selective Ipilimumab variant Ipi.105 in complex with CTLA-4

Structural highlights

7su0 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.41Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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^[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
↑ 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. Improved therapeutic index of an acidic pH-selective antibody. MAbs. 2022 Jan-Dec;14(1):2024642. PMID:35192429 doi:10.1080/19420862.2021.2024642

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7su0"

Categories: Homo sapiens | Large Structures | Chau B | Lee PS | Strop P

@@ Line 1: / Line 1: @@
-====
+==Crystal structure of an acidic pH-selective Ipilimumab variant Ipi.105 in complex with CTLA-4==
-<StructureSection load='7su0' size='340' side='right'caption='[[7su0]]' scene=''>
+<StructureSection load='7su0' size='340' side='right'caption='[[7su0]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7su0]] 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=7SU0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SU0 FirstGlance]. <br>
-</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=7su0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7su0 OCA], [https://pdbe.org/7su0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7su0 RCSB], [https://www.ebi.ac.uk/pdbsum/7su0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7su0 ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.41&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=7su0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7su0 OCA], [https://pdbe.org/7su0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7su0 RCSB], [https://www.ebi.ac.uk/pdbsum/7su0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7su0 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 7su0" 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: Z-disk]]
+[[Category: Chau B]]
+[[Category: Lee PS]]
+[[Category: Strop P]]

7su0

From Proteopedia

Revision as of 16:54, 18 October 2023

Crystal structure of an acidic pH-selective Ipilimumab variant Ipi.105 in complex with CTLA-4

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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