Cannabinoid CB1 receptor ligand binding and function examined through mutagenesis studies of F200 and S383

Sitkoff, Doree; Liao, Ning; Ellsworth, Bruce A.; Huang, Qi; Kang, Liya; Baska, RoseAnn; Huang, Yanting; Sun, Chuanyu; Pendri, Annapurna; Malley, Mary F.; Scaringe, Raymond P.; Gougoutas, Jack Z.; Reggio, Patricia H.; Ewing, William R.; Pelleymounter, Mary Ann; Carlson, Kenneth E.

doi:10.1016/j.ejphar.2010.10.056

Cited by 13 publications

(18 citation statements)

References 21 publications

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“…Experimental studies suggested that F3. 36(200) and W5.43(279) play critical roles in providing bulky groups for WIN55212-2 binding [25]. When the aromatic residues F3.36(200), W5.43(279), and W6.48(356) were replaced by alanine, the binding of both WIN55212-2 and SR141716A to CB1 receptor was significantly reduced [54].…”

Section: Cb1 Model Trained By Win55212-2mentioning

confidence: 99%

“…MD simulations of CB1 receptor embedded in a lipid bilayer have been used to gain insight into the interhelical and protein-ligand interactions [17,20,21]. Because we lack ligand-CB1 receptor experimental structures, mutation experiments are commonly used to help determine functional residues that affect ligand binding and can be guidelines to evaluate modeling results [9,[22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

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Ligand-specific homology modeling of human cannabinoid (CB1) receptor

Chang

2012

Journal of Molecular Graphics and Modelling

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Section: Cb1 Model Trained By Win55212-2mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ligand-specific homology modeling of human cannabinoid (CB1) receptor

Chang

2012

Journal of Molecular Graphics and Modelling

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“…Consistent with the inactive and active state CB1 crystal structures, the modeling study suggested that F3.36/W6.48 contact is broken during activation with a rotameric change of the χ1 dihedral of F3.36 from trans in the inactive state to g+ upon activation. The F3.36A CB1 mutation resulted in increased basal signaling of the receptor and did not affect the CP55940 dissociation constant, but reduced the binding affinity of SR141716A [16,46,57,58]. An F3.36L mutation generally restored the binding affinity of SR141716A to the receptor [57].…”

Section: W648 F336: the Rotamer Toggle Switchmentioning

confidence: 92%

Structural Insights from Recent CB1 X-Ray Crystal Structures

Al-Zoubi¹,

Hurst²,

Reggio³

2019

Recent Advances in Cannabinoid Research

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Over the past 2 years, X-ray crystal structures of the antagonist-and agonist-bound CB1 receptor have been reported. Such structures are expected to accelerate progress in the understanding of CB1 and should provide an exceptional starting point for structurebased drug discovery. This chapter examines the consistency of these X-ray structures with the CB1 experimental literature, including mutation, NMR and covalent labeling studies. These comparisons reveal discrepancies between this literature and the TMH1-2-3 region of each CB1 crystal structure. The chapter also examines crystal packing issues with each X-ray structure and shows that the discrepancies with the experimental literature can be attributed to crystal packing problems that force the N-terminus deep in the binding pocket of the two inactive state structures and force TMH2 to bend at G2.53/ S2.54 and invade the binding pocket in the activated state structure. Revision is advisable before these structures are used for structure-based drug discovery.

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“…4A). The three compounds of interest were manually docked into the human CB 1 R model, taking into account the binding affinity data of rimonabant and other inverse agonists on CB 1 R mutants, such as W279A (Sitkoff et al, 2011) and S383A (Kapur et al, 2007;Lin et al, 2008). Figure 4 depicts the putative binding modes of rimonabant and 14h and suggests that Ser383 can H-bond to the nitrogen of the pyridine ring of 14h.…”

Section: Resultsmentioning

confidence: 99%

Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists

et al. 2015

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6-Alkoxy-5-aryl-3-pyridincarboxamides, including the brain-, have been recently introduced as selective, high-affinity antagonists of the human cannabinoid-1 receptor (hCB 1 R). Binding analyses revealed two orders of magnitude lower affinity of these compounds for mouse and rat versus human CB 1 R, whereas the affinity of rimonabant is comparable for all three CB 1 Rs. Modeling of ligand binding to CB 1 R and binding assays with native and mutant (Ile105Met) hCB 1 Rs indicate that the Ile105 to Met mutation in rodent CB 1 Rs accounts for the species-dependent affinity of 14g and 14h. Our work identifies Ile105 as a new pharmacophore component for developing better hCB 1 R antagonists and invalidates rodent models for assessing the antiobesity efficacy of 14g and 14h.

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Cannabinoid CB1 receptor ligand binding and function examined through mutagenesis studies of F200 and S383

Cited by 13 publications

References 21 publications

Ligand-specific homology modeling of human cannabinoid (CB1) receptor

Ligand-specific homology modeling of human cannabinoid (CB1) receptor

Structural Insights from Recent CB1 X-Ray Crystal Structures

Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists

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