Structure, function and regulation of the melanocortin receptors.
Structure, function and regulation of the melanocortin receptors.
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DOI：
10.1016/j.ejphar.2010.12.020
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发表时间：
2011-06-11
影响因子：
5
通讯作者：
Yang, Yingkui
中科院分区：
文献类型：
--
作者：
Yang, Yingkui
黑素皮质素受体属于七跨膜（TM）结构域蛋白，与g蛋白偶联并通过细胞内环腺苷单磷酸信号传导。在黑素皮质素受体中发现了许多在其他g蛋白偶联受体（gpcr）中保守的结构特征。有五种黑素皮质素受体亚型，每种黑素皮质素受体亚型都有不同的组织表达模式，并且在不同黑素皮质素肽的相对效力方面有自己的概况。α-、β-和γ-MSH和ACTH是已知的黑素皮质素受体的内源性激动剂配体。Agouti和AgRP是已知的唯一天然存在的黑素皮质素受体拮抗剂。我们使用嵌合和突变受体检测了所有五种人类黑素皮质素受体不同配体结合亲和力和效力的分子基础。我们的研究表明，人黑素皮质素MC1受体、人黑素皮质素MC3受体、人黑素皮质素MC4受体和人黑素皮质素MC5受体利用正构位进行非选择性激动剂α-MSH和NDP- β-MSH的高亲和力结合，利用变构位进行选择性激动剂或拮抗剂的结合。此外，我们的研究结果表明，人黑素皮质素MC2受体与ACTH结合和信号传导的分子决定因素与其他黑素皮质素受体不同。许多研究还表明，即使受体表达水平和刺激-反应耦合强度相同，激动剂也能诱导黑素皮质素受体的不同构象变化，从而导致不同信号通路的激活。这一发现可能为黑素皮质素受体靶向药物的设计提供新的信息。
Melanocortin receptors belong to the seven-transmembrane (TM) domain proteins that are coupled to G-proteins and signaled through intracellular cyclic adenosine monophosphate. Many structural features conserved in other G-protein coupled receptors (GPCRs) are found in the melanocortin receptors. There are five melanocortin receptor subtypes and each of the melanocortin receptor subtypes has a different pattern of tissue expression and has its own profile regarding the relative potency of different melanocortin peptides. α-, β-, and γ-MSH and ACTH are known endogenous agonist ligands for the melanocortin receptors. Agouti and AgRP are the only known naturally occurring antagonists of the melanocortin receptors. We have examined the molecular basis of all five human melanocortin receptors for different ligand binding affinity and potency using chimeric and mutated receptors. Our studies indicate that human melanocortin MC1 receptor, human melanocortin MC3 receptor, human melanocortin MC4 receptor and human melanocortin MC5 receptor utilize orthosteric sites for non selective agonists, α-MSH and NDP- β-MSH, high affinity binding and utilize allosteric sites for selective agonist or antagonist binding. Furthermore, our results indicate that molecular determinants of human melanocortin MC2 receptor for ACTH binding and signaling are different from that of other melanocortin receptors. Many studies also indicate that agonists can induce different conformation changes of melanocortin receptors, which then lead to the activation of different signaling pathways, even when the expression level of receptor and the strength of stimulus-response coupling are the same. This finding may provide new information for the design of drugs for targeting melanocortin receptors.
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影响因子：
2.9
作者：
Chen, Min;Aprahamian, Charles J.;Yang, Yingkui
通讯作者：
Yang, Yingkui
影响因子：
3
作者：
Chen, AS;Metzger, JM;Van der Ploeg, LHT
通讯作者：
Van der Ploeg, LHT
影响因子：
56.9
作者：
MOUNTJOY, KG;ROBBINS, LS;CONE, RD
通讯作者：
CONE, RD
DOI：
10.1152/ajpregu.2001.281.2.r444
发表时间：
2001-08-01
影响因子：
2.8
作者：
Hwa, JJ;Ghibaudi, L;Parker, EM
通讯作者：
Parker, EM
影响因子：
7.3
作者：
Hogan, K;Peluso, S;Visiers, I
通讯作者：
Visiers, I