Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling

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• 作者：Fabien Plisson^a ; ¹ ; Timothy A. Hill^a ; ¹ ; ^{t.hill@imb.uq.edu.au} ; Justin M. Mitchell^a ; Huy N. Hoang^a ; Aline D. de Araujo^a ; Weijun Xu^a ; Adam Cotterell^a ; David J. Edmonds^b ; Robert V. Stanton^b ; David R. Derksen^c ; Paula M. Loria^c ; David A. Griffith^b ; David A. Price^b ; Spiros Liras^b ; David P. Fairlie^a ; ^{d.fairlie@imb.uq.edu.au}
• 关键词：GLP-1 ; α-helix ; Beta arrestin-2 ; Insulin-release ; Diabetes
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：127
• 期：Complete
• 页码：703-714
• 全文大小：2059 K
• 卷排序：127

文摘

Modeling and NMR studies of GLP-1 suggest a b-turn between Glu9-Phe12 and a kinked alpha helix between Val16-Gly37. Helix-inducing constraints and amino acid substitutions (Tyr16, Ala22) increased both peptide helicity and cAMP potency. Strong correlation was observed for binding affinity with b-arrestin 2 signalling(rs = 0.94) than cAMP stimulation(rs = 0.64). Increased insulin secretion correlated well with helicity and cAMP activity rather than with b-arrestin 2 signaling.