Increased slow dynamics defines ligandability of BTB domains.

Autor: Kharchenko V; Smart Health Initiative (SHI), Red Sea Research Center (RSRC), Bioscience Program, Biological and Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), 23955-6900, Thuwal, Saudi Arabia., Linhares BM; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI, 48108, USA.; Siduma Therapeutics, Inc., 55 Church St., 8th Fl., New Haven, CT, 06510, USA., Borregard M; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI, 48108, USA., Czaban I; Smart Health Initiative (SHI), Red Sea Research Center (RSRC), Bioscience Program, Biological and Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), 23955-6900, Thuwal, Saudi Arabia., Grembecka J; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI, 48108, USA., Jaremko M; Smart Health Initiative (SHI), Red Sea Research Center (RSRC), Bioscience Program, Biological and Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), 23955-6900, Thuwal, Saudi Arabia., Cierpicki T; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI, 48108, USA. tomaszc@umich.edu., Jaremko Ł; Smart Health Initiative (SHI), Red Sea Research Center (RSRC), Bioscience Program, Biological and Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), 23955-6900, Thuwal, Saudi Arabia. lukasz.jaremko@kaust.edu.sa.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Nov 16; Vol. 13 (1), pp. 6989. Date of Electronic Publication: 2022 Nov 16.
DOI: 10.1038/s41467-022-34599-6
Abstrakt: Efficient determination of protein ligandability, or the propensity to bind small-molecules, would greatly facilitate drug development for novel targets. Ligandability is currently assessed using computational methods that typically consider the static structural properties of putative binding sites or by experimental fragment screening. Here, we evaluate ligandability of conserved BTB domains from the cancer-relevant proteins LRF, KAISO, and MIZ1. Using fragment screening, we discover that MIZ1 binds multiple ligands. However, no ligands are uncovered for the structurally related KAISO or LRF. To understand the principles governing ligand-binding by BTB domains, we perform comprehensive NMR-based dynamics studies and find that only the MIZ1 BTB domain exhibits backbone µs-ms time scale motions. Interestingly, residues with elevated dynamics correspond to the binding site of fragment hits and recently defined HUWE1 interaction site. Our data argue that examining protein dynamics using NMR can contribute to identification of cryptic binding sites, and may support prediction of the ligandability of novel challenging targets.
(© 2022. The Author(s).)
Databáze: MEDLINE
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