The structural basis of compstatin activity examined by structure-function-based design of peptide analogs and NMR

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dc.contributor.authorMorikis, D.en
dc.contributor.authorRoy, M.en
dc.contributor.authorSahu, A.en
dc.contributor.authorTroganis, A.en
dc.contributor.authorJennings, P. A.en
dc.contributor.authorTsokos, G. C.en
dc.contributor.authorLambris, J. D.en
dc.date.accessioned2015-11-24T16:32:48Z
dc.date.available2015-11-24T16:32:48Z
dc.identifier.issn0021-9258-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/7589
dc.rightsDefault Licence-
dc.subjectcomplement inhibitoren
dc.subject2 partsen
dc.subjectactivationen
dc.subjectbiologyen
dc.subjectc3en
dc.subjectconformationsen
dc.subjectimmunologyen
dc.subjectproteinsen
dc.titleThe structural basis of compstatin activity examined by structure-function-based design of peptide analogs and NMRen
heal.abstractWe have previously identified compstatin, a 13-residue cyclic peptide, that inhibits complement activation by binding to C3 and preventing C3 cleavage to C3a and C3b. The structure of compstatin consists of a disulfide bridge and a type I beta-turn located at opposite sides to each other. The disulfide bridge is part of a hydrophobic cluster, and the beta-turn is part of a polar surface. We present the design of compstatin analogs in which we have introduced a series of perturbations in key structural elements of their parent peptide, compstatin. We have examined the consistency of the structures of the designed analogs compared with compstatin using NMR, and we have used the resulting structural information to make structure-complement inhibitory activity correlations. We propose the following. 1) Even in the absence of the disulfide bridge, a linear analog has a propensity for structure formation consistent with a turn of a 3(10)-helix or a beta-turn. 2) The type I beta-turn is a necessary but not a sufficient condition for activity. 3) Our substitutions outside the type I beta-turn of compstatin have altered the turn population but not the turn structure. 4) Flexibility of the beta-turn is essential for activity. 5) The type I beta-turn introduces reversibility and sufficiently separates the two sides of the peptide, whereas the disulfide bridge prevents the termini from drifting apart, thus aiding in the formation of the hydrophobic cluster. 6) The hydrophobic cluster at the linked termini is involved in binding to C3 and activity but alone is not sufficient for activity. 7) beta-Turn residues Gln(5) (Asn(5))-Asp(6)-Trp(7)(Phe(7)) -Gly(8) are specific for the turn formation, but only Gln(5)(Asn(5)) -Asp(6)-Trp(7)-Gly(8) residues are specific for activity. 8) Trp(7) is likely to be involved in direct interaction with C3, possibly through the formation of a hydrogen bond. Finally we propose a binding model for the C3-compstatin complex.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primaryDOI 10.1074/jbc.M200021200-
heal.identifier.secondary<Go to ISI>://000175203000076-
heal.identifier.secondaryhttp://www.jbc.org/content/277/17/14942.full.pdf-
heal.journalNameJournal of Biological Chemistryen
heal.journalTypepeer reviewed-
heal.languageen-
heal.publicationDate2002-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών και Τεχνολογιών. Τμήμα Βιολογικών Εφαρμογών και Τεχνολογιώνel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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