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Conservation of the conformational dynamics and ligand binding within M49 enzyme family

Kazazić, Saša; Karačić, Zrinka; Sabljić, Igor; Agić, Dejan; Tomin, Marko; Abramić, Marija; Dadlez, Michal; Tomić, Antonija; Tomić, Sanja (2018) Conservation of the conformational dynamics and ligand binding within M49 enzyme family. RSC Advances, 8 (24). pp. 13310-13322. ISSN 2046-2069

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The hydrogen deuterium exchange (HDX) mass spectrometry combined with molecular dynamics (MD) simulations was employed to investigate conformational dynamics and ligand binding within the M49 family (dipeptidyl peptidase III family). Six dipeptidyl peptidase III (DPP III) orthologues, human, yeast, three bacterial and one plant (moss) were studied. According to the results, all orthologues seem to be quite compact wherein DPP III from the thermophile Caldithrix abyssi seems to be the most compact. The protected regions are located within the two domains core and the overall flexibility profile consistent with semi-closed conformation as the dominant protein form in solution. Besides conservation of conformational dynamics within the M49 family, we also investigated the ligand, pentapeptide tynorphin, binding. By comparing HDX data obtained for unliganded protein with those obtained for its complex with tynorphin it was found that the ligand binding mode is conserved within the family. Tynorphin binds within inter-domain cleft, close to the lower domain β-core and induces its stabilization in all orthologues. Docking combined with MD simulations revealed details of the protein flexibility as well as of the enzyme–ligand interactions.

Item Type: Article
Additional Information: Authors thank Dr Bojana Vukelic for her help with the purification of recombinant proteins. This work has been supported by Croatian Science Foundation under the project "7235 Flexibility, activity and structure correlations in the dipeptidyl peptidase III family" and by European Union's Seventh Framework Programme for Research and Technological Development under grant agreement No. 316289 - InnoMol, FP7-REGPOT-2012-2013-1 and Croatian National Grid Infrastructure (CRO NGI,
Uncontrolled Keywords: dipeptidyl peptidase III ; DPP III ; hydrogen-deuterium exchange ; HDX ; MD simulations ; conformational dynamics
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Organic Chemistry and Biochemistry
Division of Physical Chemistry
Project titleProject leaderProject codeProject type
Enhancement of the Innovation Potential in SEE through new Molecular Solutions in Research and Development-INNOMOLUNSPECIFIED316289EK
Povezanost fleksibilnosti, aktivnosti i strukture u porodici dipeptidil-peptidaza III-FlAcSSanja TomićIP-2013-11-7235HRZZ
Depositing User: Marko Tomin
Date Deposited: 20 Nov 2018 09:12
DOI: 10.1039/c7ra13059g

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