2024年6月17日（月）に価値創造研究センター外国人客員教員（太田研究室受け入れ）Cheng先生（オハイオ州立大学）による講演会が行われます。

日　時：2024年6月17日（月）14:45-16:15　
場　所：情報学棟4F　第5講義室
講演者：Xiaolin Cheng先生（オハイオ州立大学　薬学部　教授）
題　目：Structural Mechanisms of SCAP Activation Mediated by Ammonia　
言　語：英語
参加登録：無料、事前参加登録不要

概　要：

Cholesterol homeostasis is regulated by the sterol regulatory element-binding protein (SREBP) pathway. with the membrane-embedded SREBP-cleavage-activating protein (SCAP) and insulin-inducible gene protein (Insig)-1/2 acting as sterol sensors. Our previous work revealed the critical role of ammonia in activating the SREBP pathway and identified a potential ammonia binding site formed by D428, S326 and S330 located at the core of the SCAP transmembrane domain1. In this presentation, I will discuss our recent molecular dynamics (MD) simulation study that elucidates the structural mechanisms by which ammonia binding may stimulate SCAP/Insig dissociation and SREBP activation. The SCAP S4 helix is thought to undergo a dynamic interconversion between two conformations: a partially unfolded, bent (inactive) state and a fully intact, straight (active) state during SCAP activation. Our simulations suggest that ammonia acts as an agonist of SCAP, while 25-hydroxycholesterol (25-HC) functions as an antagonist, stabilizing the active and inactive states of SCAP, respectively. Notably, ammonia operates as a hinge connecting the S3 and S6 helices, facilitating their coordinated movement. This hinge is critical for propagating the conformational transition of the S4 helix throughout the SCAP transmembrane domain, inducing alterations in the orientation and structure of the S3 and S6 helices. These structural changes lead to a decreased interaction interface contact area between SCAP and Insig and the repositioned MELADL motif at the membrane surface. Collectively, our findings reveal the intricate interplay between 25-HC and ammonia binding and the conformational transition of the SCAP S4 helix, underscoring the pivotal role of the S4 helix in SCAP activation.
1. Cheng C, Geng F, Li Z, Zhong Y, Wang H, Cheng X, Zhao Y, Mo X, Horbinski C, Duan W, Chakravarti A, Cheng X & Guo D. Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth. Nature metabolism. 2022 May;4(5):575-88.


略　歴：
創薬分野では、従来から薬剤研究者により治療薬候補となる分子を設計し合成する技術が研究されてきたが、試行錯誤による医薬品設計では、上市に至る治療薬候補が極端に少なく、その開発には膨大な時間とコストがかかることが大きな問題として知られていた。最近のコンピューター支援医薬品設計(CADD: Computer Aided Drug Design)は、データマイニングや機械学習などの情報学的な手法を採り入れて創薬の成功率と開発期間・コストを大きく改善することが期待されており、Xiaolin Cheng教授はこの分野で国際的に活躍する研究者の1人である。