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

机译：M49酶家族中的构象动力学和配体结合的保守性

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摘要

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.
机译：氢氘交换（HDX）质谱结合分子动力学（MD）模拟用于研究M49家族（二肽基肽酶III家族）中的构象动力学和配体结合。研究了六种二肽基肽酶III（DPP III）直向同源物，人类，酵母菌，三种细菌和一种植物（苔藓）。根据结果​​，所有直向同源物似乎都非常紧凑，其中来自嗜热菌Caldithrix abyssi的DPP III似乎是最紧凑的。保护区位于两个结构域的核心内，总体柔韧性与半封闭构型一致，作为溶液中的主要蛋白质形式。除了保留M49家族中的构象动力学外，我们还研究了配体五肽强啡肽的结合。通过比较从未结合的蛋白质获得的HDX数据与从其与强啡肽复合物获得的HDX数据，发现该家族中的配体结合模式是保守的。泰诺啡在域间裂隙内结合，靠近下部域β-核，并在所有直向同源物中诱导其稳定。对接与MD模拟相结合揭示了蛋白质柔韧性以及酶与配体相互作用的细节。

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