7AXU

Structure of WDR5:CS-VIP8 cocrystal after illumination in situ

Summary for 7AXU

• Entry DOI: 10.2210/pdb7axu/pdb
• Related: 7AXP 7AXQ 7AXS
• Descriptor: WD repeat-containing protein 5 (2 entities in total)
• Functional Keywords: wdr5, cyclic strained visible-light photoswitches, mll1 complex disruption, inhibition of hematopoiesis, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36635.44

Authors

Werel, L.,Essen, L.-O. (deposition date: 2020-11-10, release date: 2021-11-24, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.68 Å)