Binding Hotspots of BAZ2B Bromodomain: Histone Interaction Revealed by Solution NMR Driven Docking

Fleur M. Ferguson; David M. Dias; João Garcia Lopes Maia Rodrigues; Hans Wienk; Rolf Boelens; Alexandre M. J. J. Bonvin; Chris Abell; Alessio Ciulli

doi:10.1021/bi500909d

Binding Hotspots of BAZ2B Bromodomain: Histone Interaction Revealed by Solution NMR Driven Docking

Fleur M. Ferguson, David M. Dias, João Garcia Lopes Maia Rodrigues, Hans Wienk, Rolf Boelens, Alexandre M. J. J. Bonvin, Chris Abell, Alessio Ciulli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Bromodomains are epigenetic reader domains, which have come under increasing scrutiny both from academic and pharmaceutical research groups. Effective targeting of the BAZ2B bromodomain by small molecule inhibitors has been recently reported, but no structural information is yet available on the interaction with its natural binding partner, acetylated histone H3K14ac. We have assigned the BAZ2B bromodomain and studied its interaction with H3K14ac acetylated peptides by NMR spectroscopy using both chemical shift perturbation (CSP) data and clean chemical exchange (CLEANEX-PM) NMR experiments. The latter was used to characterize water molecules known to play an important role in mediating interactions. Besides the anticipated Kac binding site, we consistently found the bromodomain BC loop as hotspots for the interaction. This information was used to create a data-driven model for the complex using HADDOCK. Our findings provide both structure and dynamics characterization that will be useful in the quest for potent and selective inhibitors to probe the function of the BAZ2B bromodomain.

Original language	English
Pages (from-to)	6706-6716
Number of pages	11
Journal	Biochemistry
Volume	53
Issue number	42
DOIs	https://doi.org/10.1021/bi500909d
Publication status	Published - 28 Oct 2014

Funding

This work was supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC, Grants BB/J00-1201/1 and David Phillips Fellowship BB/G023123/1 to A.G.). F.M.F. is funded by a BBSRC Ph.D studentship. D.M.D. acknowledges the Fundacao para a Ciencia e a Tecnologia (FCT, SFRH/BD/81735/2011 Studentship). J.P.G.L.M. and A.M.J.J.B. acknowledge the financial support from Utrecht University (Focus and Massa Programme) and The Netherlands Organization for Scientific Research (VICI Grant No. 700.56.442). Financial support by the European Union (Bio-NMR, Project 261863) for access to the SONNMR Large-Scale Facility in Utrecht (The Netherlands) is gratefully acknowledged.

Keywords

MOLECULAR SIMULATION
RECOGNITION
RELAXATION
EFFICIENT
PROTEINS
INSIGHTS
HADDOCK
FAMILY
GENES
H3

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title = "Binding Hotspots of BAZ2B Bromodomain: Histone Interaction Revealed by Solution NMR Driven Docking",

abstract = "Bromodomains are epigenetic reader domains, which have come under increasing scrutiny both from academic and pharmaceutical research groups. Effective targeting of the BAZ2B bromodomain by small molecule inhibitors has been recently reported, but no structural information is yet available on the interaction with its natural binding partner, acetylated histone H3K14ac. We have assigned the BAZ2B bromodomain and studied its interaction with H3K14ac acetylated peptides by NMR spectroscopy using both chemical shift perturbation (CSP) data and clean chemical exchange (CLEANEX-PM) NMR experiments. The latter was used to characterize water molecules known to play an important role in mediating interactions. Besides the anticipated Kac binding site, we consistently found the bromodomain BC loop as hotspots for the interaction. This information was used to create a data-driven model for the complex using HADDOCK. Our findings provide both structure and dynamics characterization that will be useful in the quest for potent and selective inhibitors to probe the function of the BAZ2B bromodomain.",

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author = "Ferguson, {Fleur M.} and Dias, {David M.} and {Garcia Lopes Maia Rodrigues}, Jo{\~a}o and Hans Wienk and Rolf Boelens and Bonvin, {Alexandre M. J. J.} and Chris Abell and Alessio Ciulli",

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T2 - Histone Interaction Revealed by Solution NMR Driven Docking

AU - Ferguson, Fleur M.

AU - Dias, David M.

AU - Garcia Lopes Maia Rodrigues, João

AU - Wienk, Hans

AU - Boelens, Rolf

AU - Bonvin, Alexandre M. J. J.

AU - Abell, Chris

AU - Ciulli, Alessio

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N2 - Bromodomains are epigenetic reader domains, which have come under increasing scrutiny both from academic and pharmaceutical research groups. Effective targeting of the BAZ2B bromodomain by small molecule inhibitors has been recently reported, but no structural information is yet available on the interaction with its natural binding partner, acetylated histone H3K14ac. We have assigned the BAZ2B bromodomain and studied its interaction with H3K14ac acetylated peptides by NMR spectroscopy using both chemical shift perturbation (CSP) data and clean chemical exchange (CLEANEX-PM) NMR experiments. The latter was used to characterize water molecules known to play an important role in mediating interactions. Besides the anticipated Kac binding site, we consistently found the bromodomain BC loop as hotspots for the interaction. This information was used to create a data-driven model for the complex using HADDOCK. Our findings provide both structure and dynamics characterization that will be useful in the quest for potent and selective inhibitors to probe the function of the BAZ2B bromodomain.

AB - Bromodomains are epigenetic reader domains, which have come under increasing scrutiny both from academic and pharmaceutical research groups. Effective targeting of the BAZ2B bromodomain by small molecule inhibitors has been recently reported, but no structural information is yet available on the interaction with its natural binding partner, acetylated histone H3K14ac. We have assigned the BAZ2B bromodomain and studied its interaction with H3K14ac acetylated peptides by NMR spectroscopy using both chemical shift perturbation (CSP) data and clean chemical exchange (CLEANEX-PM) NMR experiments. The latter was used to characterize water molecules known to play an important role in mediating interactions. Besides the anticipated Kac binding site, we consistently found the bromodomain BC loop as hotspots for the interaction. This information was used to create a data-driven model for the complex using HADDOCK. Our findings provide both structure and dynamics characterization that will be useful in the quest for potent and selective inhibitors to probe the function of the BAZ2B bromodomain.

KW - MOLECULAR SIMULATION

KW - RECOGNITION

KW - RELAXATION

KW - EFFICIENT

KW - PROTEINS

KW - INSIGHTS

KW - HADDOCK

KW - FAMILY

KW - GENES

KW - H3

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JO - Biochemistry

JF - Biochemistry

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ER -

Binding Hotspots of BAZ2B Bromodomain: Histone Interaction Revealed by Solution NMR Driven Docking

Abstract

Funding

Keywords

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