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Binding Motifs in the CBP Bromodomain: An Analysis of 20 Crystal Structures of Complexes with Small Molecules


Zhu, Jian; Dong, Jing; Batiste, Laurent; Unzue, Andrea; Dolbois, Aymeric; Pascanu, Vlad; Śledź, Paweł; Nevado, Cristina; Caflisch, Amedeo (2018). Binding Motifs in the CBP Bromodomain: An Analysis of 20 Crystal Structures of Complexes with Small Molecules. ACS Medicinal Chemistry Letters, 9(9):929-934.

Abstract

We analyze 20 crystal structures of complexes between the CBP bromodomain and small-molecule ligands that belong to eight different chemotypes identified by docking. The binding motif of the moiety that mimics the natural ligand (acetylated side chain of lysine) at the bottom of the binding pocket is conserved. In stark contrast, the rest of the ligands form different interactions with different side chains and backbone polar groups on the outer rim of the binding pocket. Hydrogen bonds are direct or water-bridged. van der Waals contacts are optimized by rotations of hydrophobic side chains and a slight inward displacement of the ZA loop. Rare types of interactions are observed for some of the ligands.

Abstract

We analyze 20 crystal structures of complexes between the CBP bromodomain and small-molecule ligands that belong to eight different chemotypes identified by docking. The binding motif of the moiety that mimics the natural ligand (acetylated side chain of lysine) at the bottom of the binding pocket is conserved. In stark contrast, the rest of the ligands form different interactions with different side chains and backbone polar groups on the outer rim of the binding pocket. Hydrogen bonds are direct or water-bridged. van der Waals contacts are optimized by rotations of hydrophobic side chains and a slight inward displacement of the ZA loop. Rare types of interactions are observed for some of the ligands.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:13 September 2018
Deposited On:07 Dec 2018 14:07
Last Modified:08 Feb 2019 12:32
Publisher:American Chemical Society (ACS)
ISSN:1948-5875
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1021/acsmedchemlett.8b00286
PubMed ID:30258543

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