(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition

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Andersson, Ida E.,1982-Umeå universitet,Kemiska institutionen (author)

(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition

Article/chapterEnglish2011

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2011-08-19
American Chemical Society,2011
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LIBRIS-ID:oai:DiVA.org:umu-42072
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-42072URI
https://doi.org/10.1021/ja2038722DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:123280016URI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.

Subject headings and genre

NATURVETENSKAP Kemi hsv//swe
NATURAL SCIENCES Chemical Sciences hsv//eng
Chemistry
Kemi

Added entries (persons, corporate bodies, meetings, titles ...)

Batsalova, TsvetelinaMedical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet (author)
Haag, SabrinaKarolinska Institutet (author)
Dzhambazov, BalikMedical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet (author)
Holmdahl, RikardKarolinska Institutet (author)
Kihlberg, Jan,1957-Umeå universitet,Kemiska institutionen(Swepub:umu)jaki0001 (author)
Linusson, Anna,1970-Umeå universitet,Kemiska institutionen(Swepub:umu)analin99 (author)
Umeå universitetKemiska institutionen (creator_code:org_t)

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In:Journal of the American Chemical Society: American Chemical Society133:36, s. 14368-143780002-78631520-5126

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