Molecular characterization of human melanocortin-5 receptor ligand-receptor interaction.
Molecular characterization of human melanocortin-5 receptor ligand-receptor interaction.
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DOI：
10.1021/bi3013593
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发表时间：
2013-02
期刊：
影响因子：
2.9
通讯作者：
Ying-kui Yang;V. Mishra;Min Chen;Elaine Duffee;R. Dimmitt;C. Harmon
中科院分区：
文献类型：
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作者：
Ying-kui Yang;V. Mishra;Min Chen;Elaine Duffee;R. Dimmitt;C. Harmon
黑皮质素-5受体（MC 5 R）是黑皮质素受体（MCR）家族的一种亚型受体，其在中枢以及多种外周组织中表达。MC 5 R参与许多不同的生理学领域，如脂质代谢和外分泌功能。然而，负责配体结合和受体信号传导的MC 5 R的特定分子决定簇目前尚不清楚。本研究的目的是确定人MC 5 R（hMC 5 R）负责配体结合和受体信号传导的分子基础。产生并测试了hMC 5 R的24个单突变。我们的研究结果表明：（1）用丙氨酸取代跨膜结构域2（TM 2）中的带电荷氨基酸残基E92，TM 3中的天冬氨酸115（D115）和D119，以及TM 6中的组氨酸（H）257，显著降低了NDP-α-MSH结合亲和力和受体信号传导;（2）用芳香族氨基酸取代TM 5中的苯丙氨酸（F）195，TM 6中的F254，而H276则显著降低了NDP-α-MSH结合和受体活性。结合药理学结果和计算机模拟，我们的结果表明TM 3中的D115和D119，TM 5中的F195和TM 6中的F254可能形成NDP-α-MSH结合的结合口袋。我们的研究结果提供了重要的信息，负责配体结合和受体信号的hMC 5 R的结构方面。
The melanocortin-5 receptor (MC5R) is a subtype receptor of the melanocortin receptor (MCR) family, which is expressed centrally, as well as in a variety of peripheral tissues. MC5R has been implicated in many different physiological fields such as lipid metabolism and exocrine function. However, the specific molecular determinants of MC5R responsible for ligand binding and receptor signaling are currently unknown. The aim of this study is to determine the molecular basis of human MC5R (hMC5R) responsible for ligand binding and receptor signaling. Twenty-four single mutations of hMC5R were created and tested. Our results indicate that (1) substituting charged amino acid residue E92 in transmembrane domain 2 (TM2), aspartic acid 115 (D115) and D119 in TM3, and histidine (H) 257 in TM6 with alanine dramatically reduced NDP-α-MSH binding affinity and receptor signaling and (2) substituting aromatic amino acids phenylalanine (F) 195 in TM5, F254 in TM6, and H276 in TM7 with alanine also significantly decreased NDP-α-MSH binding and receptor activity. Combining pharmacological results and computer modeling, our results suggest that D115 and D119 in TM3, F195 in TM5, and F254 in TM6 may form a binding pocket for NDP-α-MSH binding. Our results provide important information about the structural aspects of hMC5R responsible for ligand binding and receptor signaling.