National Health and Medical Research Council (NHMRC, Australia)
1120919
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1159006
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1150083
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1154434
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1155302
オーストラリア
Japan Science and Technology
18069571
日本
Takeda Science Foundation
2019 Medical Research Grant
日本
引用
ジャーナル: Nat Chem Biol / 年: 2024 タイトル: Structural insight into selectivity of amylin and calcitonin receptor agonists. 著者: Jianjun Cao / Matthew J Belousoff / Elliot Gerrard / Radostin Danev / Madeleine M Fletcher / Emma Dal Maso / Herman Schreuder / Katrin Lorenz / Andreas Evers / Garima Tiwari / Melissa ...著者: Jianjun Cao / Matthew J Belousoff / Elliot Gerrard / Radostin Danev / Madeleine M Fletcher / Emma Dal Maso / Herman Schreuder / Katrin Lorenz / Andreas Evers / Garima Tiwari / Melissa Besenius / Ziyu Li / Rachel M Johnson / Denise Wootten / Patrick M Sexton / 要旨: Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is ...Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formation of a 'bypass' secondary structural motif (residues S19-P25). This study explored potential tuning of peptide selectivity through modification to residues 19-22, resulting in a selective AMYR agonist, San385, as well as nonselective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMYR, and San45 bound to AMYR or CTR. San45, via its conjugated lipid at position 21, was anchored at the edge of the receptor bundle, enabling a stable, alternative binding mode when bound to the CTR, in addition to the bypass mode of binding to AMYR. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.
名称: N-hexadecanoyl-L-glutamic acid / タイプ: ligand / ID: 7 詳細: Its an analogue derived from pramlintide by adding a lipid modification on the position 21 of lysine コピー数: 1 / 式: D6M