Structural mechanism of CB1R binding to peripheral and biased inverse agonists

被引:1
|
作者
Kumari, Punita [1 ,6 ]
Dvoracsko, Szabolcs [2 ,3 ,4 ,7 ]
Enos, Michael D. [1 ]
Ramesh, Karthik [1 ]
Lim, Darrix [1 ]
Hassan, Sergio A. [5 ]
Kunos, George [3 ]
Cinar, Resat [4 ]
Iyer, Malliga R. [2 ]
Rosenbaum, Daniel M. [1 ]
机构
[1] Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA
[2] NIAAA, Sect Med Chem, NIH, Rockville, MD 20852 USA
[3] NIAAA, Lab Physiol Studies, NIH, Rockville, MD USA
[4] NIAAA, Sect Fibrot Disorders, NIH, Rockville, MD USA
[5] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD USA
[6] Indian Inst Sci Educ & Res, Dept Biol Sci, Bhopal, Madhya Pradesh, India
[7] HUN REN Biol Res Ctr, Inst Biochem, Lab Biomol Struct & Pharmacol, Szeged, Hungary
基金
美国国家卫生研究院;
关键词
CRYSTAL-STRUCTURE; DYNAMIC PROCESS; RECEPTOR; RIMONABANT; INSIGHTS; SYNTHASE; SYSTEM;
D O I
10.1038/s41467-024-54206-0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The cannabinoid receptor 1 (CB1R) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CB1R antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted their further therapeutic development. The peripherally restricted CB1R inverse agonists MRI-1867 and MRI-1891 represent a new generation of compounds that retain the metabolic benefits of CB1R inhibitors while sparing the negative psychiatric effects. To understand the mechanism of binding and inhibition of CB1R by peripherally restricted antagonists, we developed a nanobody/fusion protein strategy for high-resolution cryo-EM structure determination of the GPCR inactive state, and used this method to determine structures of CB1R bound to either MRI-1867 or MRI-1891. These structures reveal how these compounds retain high affinity and specificity for CB1R's hydrophobic orthosteric site despite incorporating polar functionalities that lead to peripheral restriction. Further, the structure of the MRI-1891 complex along with accompanying molecular dynamics simulations shows how differential engagement with transmembrane helices and the proximal N-terminus can propagate through the receptor to contribute to biased inhibition of beta-arrestin signaling.
引用
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页数:13
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