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dc.contributor.authorKharchenko, Vladlena
dc.contributor.authorLinhares, Brian M.
dc.contributor.authorBorregard, Megan
dc.contributor.authorCzaban, Iwona
dc.contributor.authorGrembecka, Jolanta
dc.contributor.authorJaremko, Mariusz
dc.contributor.authorCierpicki, Tomasz
dc.contributor.authorJaremko, Lukasz
dc.date.accessioned2022-11-16T10:32:03Z
dc.date.available2022-11-16T10:32:03Z
dc.date.issued2022-11-16
dc.identifier.citationKharchenko, V., Linhares, B. M., Borregard, M., Czaban, I., Grembecka, J., Jaremko, M., Cierpicki, T., & Jaremko, Ł. (2022). Increased slow dynamics defines ligandability of BTB domains. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-34599-6
dc.identifier.issn2041-1723
dc.identifier.doi10.1038/s41467-022-34599-6
dc.identifier.urihttp://hdl.handle.net/10754/685778
dc.description.abstractEfficient 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.
dc.description.sponsorshipThis publication is based upon work supported by the King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) under Award No. OSR-CRG2018-3792 and Award No. OSR-CRG2019-4088 (L.J.). This work was funded by the National Institute of Health (NIH) R01 grant CA207272 (T.C.) and T.C. is a Rogel Scholar. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817).
dc.publisherSpringer Science and Business Media LLC
dc.relation.urlhttps://www.nature.com/articles/s41467-022-34599-6
dc.rightsArchived with thanks to Nature Communications under a Creative Commons license, details at: https://creativecommons.org/licenses/by/4.0
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleIncreased slow dynamics defines ligandability of BTB domains
dc.typeArticle
dc.contributor.departmentSmart 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
dc.contributor.departmentBioscience
dc.contributor.departmentBiological and Environmental Science and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.contributor.departmentRed Sea Research Center (RSRC)
dc.identifier.journalNature Communications
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionDepartment of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI, 48108, USA
dc.contributor.institutionSiduma Therapeutics, Inc., 55 Church St., 8th Fl., New Haven, CT, 06510, USA
dc.identifier.volume13
dc.identifier.issue1
kaust.personKharchenko, Vladlena
kaust.personCzaban, Iwona
kaust.personJaremko, Mariusz
kaust.personJaremko, Lukasz
kaust.grant.numberOSR-CRG2018-3792
kaust.grant.numberOSR-CRG2019-4088
refterms.dateFOA2022-11-16T10:33:21Z
kaust.acknowledged.supportUnitOffice of Sponsored Research (OSR)


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Archived with thanks to Nature Communications under a Creative Commons license, details at: https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as Archived with thanks to Nature Communications under a Creative Commons license, details at: https://creativecommons.org/licenses/by/4.0