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M49酶家族内构象动力学和配体结合的保守性

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

作者信息

Kazazić Saša, Karačić Zrinka, Sabljić Igor, Agić Dejan, Tomin Marko, Abramić Marija, Dadlez Michal, Tomić Antonija, Tomić Sanja

机构信息

Ruđer Bošković Institute, Institute of Biochemistry and Biophysics Polish Academy of Sciences Croatia

Josip Juraj Strossmayer University of Osijek, Faculty of Agriculture Croatia.

出版信息

RSC Adv. 2018 Apr 10;8(24):13310-13322. doi: 10.1039/c7ra13059g. eCollection 2018 Apr 9.

DOI:10.1039/c7ra13059g
PMID:35542530
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9079729/
Abstract

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 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.

摘要

采用氢氘交换（HDX）质谱联用分子动力学（MD）模拟技术，研究M49家族（二肽基肽酶III家族）的构象动力学和配体结合情况。研究了六种二肽基肽酶III（DPP III）直系同源物，包括人类、酵母、三种细菌和一种植物（苔藓）的。根据结果，所有直系同源物似乎都相当紧凑，其中嗜热菌的DPP III似乎是最紧凑的。受保护区域位于两个结构域的核心内，整体灵活性概况与半封闭构象一致，这是溶液中主要的蛋白质形式。除了M49家族内构象动力学的保守性外，我们还研究了配体五肽强啡肽的结合情况。通过比较未结合配体的蛋白质和其与强啡肽复合物获得的HDX数据，发现配体结合模式在家族内是保守的。强啡肽结合在结构域间裂隙内，靠近下部结构域β-核心，并在所有直系同源物中诱导其稳定。对接结合MD模拟揭示了蛋白质灵活性以及酶-配体相互作用的细节。

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4
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