ABCMdb

ABCC8 p.Tyr179Ala

Predicted by SNAP2:	A: D (59%), C: D (63%), D: D (59%), E: D (75%), F: D (66%), G: N (53%), H: D (63%), I: D (71%), K: D (71%), L: D (71%), M: D (71%), N: N (61%), P: D (75%), Q: D (63%), R: D (80%), S: N (53%), T: D (59%), V: D (66%), W: D (75%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: N, G: D, H: N, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D,

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Publications
[hide] The M1 muscarinic receptor allosteric agonists AC-... Mol Pharmacol. 2010 Oct;78(4):648-57. Epub 2010 Jul 21. Jacobson MA, Kreatsoulas C, Pascarella DM, O'Brien JA, Sur C
The M1 muscarinic receptor allosteric agonists AC-42 and 1-[1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one bind to a unique site distinct from the acetylcholine orthosteric site.
Mol Pharmacol. 2010 Oct;78(4):648-57. Epub 2010 Jul 21., [PMID:20660086]

Abstract [show]
Activation of M1 muscarinic receptors occurs through orthosteric and allosteric binding sites. To identify critical residues, site-directed mutagenesis and chimeric receptors were evaluated in functional calcium mobilization assays to compare orthosteric agonists, acetylcholine and xanomeline, M1 allosteric agonists AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride), TBPB (1-[1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one) , and the clozapine metabolite N-desmethylclozapine. A minimal epitope has been defined for AC-42 that comprises the first 45 amino acids, the third extracellular loop, and seventh transmembrane domain (Mol Pharmacol 61:1297-1302, 2002). Using chimeric M1 and M3 receptor constructs, the AC-42 minimal epitope has been extended to also include transmembrane II. Phe77 was identified as a critical residue for maintenance of AC-42 and TBPB agonist activity. In contrast, the functional activity of N-desmethylclozapine did not require Phe77. To further map the binding site of AC-42, TBPB, and N-desmethylclozapine, point mutations previously reported to affect activities of M1 orthosteric agonists and antagonists were studied. Docking into an M1 receptor homology model revealed that AC-42 and TBPB share a similar binding pocket adjacent to the orthosteric binding site at the opposite face of Trp101. In contrast, the activity of N-desmethylclozapine was generally unaffected by the point mutations studied, and the docking indicated that N-desmethylclozapine bound to a site distinct from AC-42 and TBPB overlapping with the orthosteric site. These results suggest that structurally diverse allosteric agonists AC-42, TBPB, and N-desmethylclozapine may interact with different subsets of residues, supporting the hypothesis that M1 receptor activation can occur through at least three different binding domains.

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No. Sentence Comment
167 In comparison, the affinity of N-desmethylclozapine was only slightly changed on W101A and W101F, where a 2-fold decrease and 1.25-fold increase in potency were measured, respectively. Substitution of Tyr179 with either alanine or phenylalanine resulted in only minor changes in functional potencies -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 Ile Phe Log [Agonist] (M) %Max -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 Asn Gly Log [Agonist] (M) %Max -10 -9 -8 -7 -6 -5 -4 -3 0 20 40 60 80 100 Asn Thr Log [Agonist] (M) %Max Ach AC42 TBPB Fig. 4. Login to comment
173 The affinity of acetylcholine was decreased by only 2.5and 2-fold on Y179A and Y179F, respectively. Login to comment
175 The affinity for AC-42 and TBPB were increased on Y179A by 1.25and 2.9-fold, respectively. Login to comment