Conformational investigation of the structure-activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit.
Conformational investigation of the structure-activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit.
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GDFFD及其类似物在喂养回路中涉及的Aplysia aplysia aplysia的神经肽受体上的结构活性关系的构象研究。
DOI：
10.1039/c8cp03661f
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发表时间：
2018-08-29
期刊：
影响因子：
--
通讯作者：
Sweedler JV
中科院分区：
文献类型：
--
作者：
Do TD ;Checco JW ;Tro M ;Shea JE ;Bowers MT ;Sweedler JV
自然界中的蛋白质和多肽几乎完全由l-氨基酸构成，在后生动物中更是如此。然而，随着现代生物分析技术的出现，以前未被认识到的d-氨基酸在生物过程中的作用已被揭示。在动物中发现了超过30种含有d-氨基酸的肽（DAACPs），其中至少有一个l-残基通过酶催化过程异构化为d-形式。在加州海杉中，GdFFD和GdYFD（小写字母“d”表示d氨基酸残基）通过激活海杉绒毛蛋白样神经肽受体（apALNR）来调节摄食行为。然而，对于DAACPs的三维构象如何影响受体的活性，以及d-残基在这些肽构象中所起的作用，人们知之甚少。在这里，我们使用计算建模、漂管离子迁移率质谱和受体激活分析相结合的方法来创建一个简单的模型，预测一系列GdFFD类似物的生物活性。我们的研究结果表明，GdFFD和GdYFD的活性构象与它们在溶液中的最低能量构象相似。我们的模型有助于将GdFFD类似物的预测结构与其活性联系起来，并强调了GdFFD受体apALNR上1位肽活性的立体效应。总的来说，这些方法使我们能够在缺乏高分辨率结构数据的情况下理解配体与受体的相互作用。计算模型和离子迁移率质谱用于了解和预测内源性d-氨基酸神经肽在其同源受体上的活性。
Proteins and peptides in nature are almost exclusively made from l-amino acids, and this is even more absolute in the metazoan. With the advent of modern bioanalytical techniques, however, previously unappreciated roles for d-amino acids in biological processes have been revealed. Over 30 d-amino acid containing peptides (DAACPs) have been discovered in animals where at least one l-residue has been isomerized to the d-form via an enzyme-catalyzed process. In Aplysia californica, GdFFD and GdYFD (the lower-case letter “d” indicates a d-amino acid residue) modulate the feeding behavior by activating the Aplysia achatin-like neuropeptide receptor (apALNR). However, little is known about how the three-dimensional conformation of DAACPs influences activity at the receptor, and the role that d-residues play in these peptide conformations. Here, we use a combination of computational modeling, drift-tube ion-mobility mass spectrometry, and receptor activation assays to create a simple model that predicts bioactivities for a series of GdFFD analogs. Our results suggest that the active conformations of GdFFD and GdYFD are similar to their lowest energy conformations in solution. Our model helps connect the predicted structures of GdFFD analogs to their activities, and highlights a steric effect on peptide activity at position 1 on the GdFFD receptor apALNR. Overall, these methods allow us to understand ligand-receptor interactions in the absence of high-resolution structural data. Computational modeling and ion-mobility mass spectrometry are used to understand and predict the activity of endogenous D-amino acid-containing neuropeptides at their cognate receptor.
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影响因子：
15
作者：
Gidden, J;Ferzoco, A;Bowers, MT
通讯作者：
Bowers, MT
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
15
作者：
Bernstein, SL;Wyttenbach, T;Bowers, MT
通讯作者：
Bowers, MT
影响因子：
8.8
作者：
Bauknecht, Philipp;Jekely, Gaspar
通讯作者：
Jekely, Gaspar
影响因子：
7.4
作者：
Jeanne Dit Fouque K;Garabedian A;Porter J;Baird M;Pang X;Williams TD;Li L;Shvartsburg A;Fernandez-Lima F
通讯作者：
Fernandez-Lima F