Hitting a Moving Target: Simulation and Crystallography Study of ATAD2 Bromodomain Blockers.

Autor:	Dolbois A; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Batiste L; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Wiedmer L; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Dong J; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Brütsch M; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Huang D; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Deerain NM; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Spiliotopoulos D; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Cheng-Sánchez I; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Laul E; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Nevado C; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Śledź P; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Caflisch A; Department of Chemistry and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Jun 30; Vol. 11 (8), pp. 1573-1580. Date of Electronic Publication: 2020 Jun 30 (Print Publication: 2020).
DOI:	10.1021/acsmedchemlett.0c00080
Abstrakt:	Small molecule ligand binding to the ATAD2 bromodomain is investigated here through the synergistic combination of molecular dynamics and protein crystallography. A previously unexplored conformation of the binding pocket upon rearrangement of the gatekeeper residue Ile1074 has been found. Further, our investigations reveal how minor structural differences in the ligands result in binding with different plasticity of the ZA loop for this difficult-to-drug bromodomain. Competing Interests: The authors declare no competing financial interest. (Copyright © 2020 American Chemical Society.)
Databáze:	MEDLINE
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