7AXP

Structural characterisation of WDR5:CS-VIP8 interaction in cis state 2

7AXP の概要

• エントリーDOI: 10.2210/pdb7axp/pdb
• 分子名称: WD repeat-containing protein 5, CS-VIP8 (3 entities in total)
• 機能のキーワード: wdr5, cyclic strained visible-light photoswitches, mll1 complex disruption, inhibition of hematopoiesis, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37579.40

構造登録者

Werel, L.,Essen, L.-O. (登録日: 2020-11-10, 公開日: 2021-12-15, 最終更新日: 2024-07-10)

主引用文献

Albert, L.,Nagpal, J.,Steinchen, W.,Zhang, L.,Werel, L.,Djokovic, N.,Ruzic, D.,Hoffarth, M.,Xu, J.,Kaspareit, J.,Abendroth, F.,Royant, A.,Bange, G.,Nikolic, K.,Ryu, S.,Dou, Y.,Essen, L.O.,Vazquez, O.
Bistable Photoswitch Allows in Vivo Control of Hematopoiesis.
Acs Cent.Sci., 8:57-66, 2022

PubMed Abstract: Optical control has enabled functional modulation in cell culture with unparalleled spatiotemporal resolution. However, current tools for in vivo manipulation are scarce. Here, we design and implement a genuine optochemical probe capable of achieving hematopoietic control in zebrafish. Our photopharmacological approach first developed conformationally strained visible light photoswitches (CS-VIPs) as inhibitors of the histone methyltransferase MLL1 (KMT2A). In blood homeostasis MLL1 plays a crucial yet controversial role. optimally fulfils the requirements of a true bistable functional system in vivo under visible-light irradiation, and with unprecedented stability. These properties are exemplified via hematopoiesis photoinhibition with a single isomer in zebrafish. The present interdisciplinary study uncovers the mechanism of action of CS-VIPs. Upon WDR5 binding, causes MLL1 release with concomitant allosteric rearrangements in the WDR5/RbBP5 interface. Since our tool provides on-demand reversible control without genetic intervention or continuous irradiation, it will foster hematopathology and epigenetic investigations. Furthermore, our workflow will enable exquisite photocontrol over other targets inhibited by macrocycles.

PubMed: 35106373
DOI: 10.1021/acscentsci.1c00434

実験手法

X-RAY DIFFRACTION (2.432 Å)