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Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis
Umea Univ, Dept Chem, SE-90187 Umea, Sweden.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 11, p. 4774-4790Article in journal (Refereed) Published
Abstract [en]

Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CI1259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CI1259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CI1259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CI1259-273, together with the positioning of the galactose moiety of CI1259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CI1259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2018. Vol. 61, no 11, p. 4774-4790
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Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-358519DOI: 10.1021/acs.jmedchem.7b01880ISI: 000435613100008PubMedID: 29727183OAI: oai:DiVA.org:uu-358519DiVA, id: diva2:1244670
Funder
Swedish Research Council, 2014-4675Swedish Research Council, 2016-05160Knut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Available from: 2018-09-03 Created: 2018-09-03 Last updated: 2018-09-03Bibliographically approved

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Tyagi, MohitViljanen, Johan V.Kihlberg, Jan

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