大麻素受体与G蛋白的相互作用：IC3及具有改变的G蛋白特异性的突变体与G（αi1）结合的结构
Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures of IC3 and a mutant with altered G protein specificity.
作者信息
Ulfers Amy L, McMurry Jonathan L, Miller Alexander, Wang Ligong, Kendall Debra A, Mierke Dale F
机构信息
Department of Molecular Pharmacology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.
出版信息
Protein Sci. 2002 Oct;11(10):2526-31. doi: 10.1110/ps.0218402.
Abstract
The structure of the C-terminal region of the third cytoplasmic loop (IC3) of the cannabinoid receptor one (CB1) bound to G(alphai1) has been determined using transferred nuclear Overhauser effects (NOEs). The wild-type IC3 sequence is helical when associated with G(alphai1). In contrast, a peptide containing the amino-acid inversion, Ala(341)-Leu(342) adopts a single turn. These findings correlate with the attenuated G(i) association of CB1 with the Ala(341)-Leu(342) mutation previously observed in vivo and the diminished stimulation of G(alphai1) GTPase activity by the corresponding peptide demonstrated in vitro here. These results, the first to report the structure of a GPCR domain while associated with G protein, imply the C-terminus of CB1 IC3, a region with high-sequence conservation among G-protein coupled receptors, must be helical for efficient coupling and activation of the G(i) protein.
摘要
通过转移核Overhauser效应（NOE）确定了与G（αi1）结合的大麻素受体1（CB1）第三细胞质环（IC3）C端区域的结构。野生型IC3序列与G（αi1）结合时呈螺旋状。相比之下，含有氨基酸倒置Ala（341）-Leu（342）的肽段呈单圈结构。这些发现与之前在体内观察到的CB1与Ala（341）-Leu（342）突变体G（i）结合减弱以及此处体外实验证明的相应肽段对G（αi1）GTP酶活性刺激减弱相关。这些结果首次报道了GPCR结构域与G蛋白结合时的结构，表明CB1 IC3的C端，即G蛋白偶联受体中具有高度序列保守性的区域，必须呈螺旋状才能有效偶联并激活G（i）蛋白。
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本文引用的文献
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2
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J Neurosci. 2001 Nov 15;21(22):8758-64. doi: 10.1523/JNEUROSCI.21-22-08758.2001.
3
Agonist-induced conformational changes in the G-protein-coupling domain of the beta 2 adrenergic receptor.β2肾上腺素能受体G蛋白偶联结构域中激动剂诱导的构象变化。
Proc Natl Acad Sci U S A. 2001 May 22;98(11):5997-6002. doi: 10.1073/pnas.101126198. Epub 2001 May 15.
4
Leptin-regulated endocannabinoids are involved in maintaining food intake.瘦素调节的内源性大麻素参与维持食物摄入量。
Nature. 2001 Apr 12;410(6830):822-5. doi: 10.1038/35071088.
5
CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains.
Eur J Biochem. 2001 Feb;268(3):499-505. doi: 10.1046/j.1432-1327.2001.01810.x.
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