title: Catalytic mechanism of histone acetyltransferase p300: from the proton transfer to acetylation reaction.
abstract: The transcriptional coactivator and histone acetyltransferase (HAT) p300 acetylates the four core histones and other transcription factors to regulate a plethora of fundamental biological processes including cell growth, development, oncogenesis and apoptosis. Recent structural and biochemical studies on the p300 HAT domain revealed a Theorell-Chance, or "hit-and-run", catalytic mechanism. Nonetheless, the chemical mechanism of the entire reaction process including the proton transfer (PT) scheme and consequent acetylation reaction route remains unclear. In this study, a combined computational strategy consisting of molecular modeling, molecular dynamic (MD) simulation, and quantum mechanics/molecular mechanics (QM/MM) simulation was applied to elucidate these important issues. An initial p300/H3/Ac-CoA complex structure was modeled and optimized using a 100 ns MD simulation. Residues that play important roles in substrate binding and the acetylation reaction were comprehensively investigated. For the first time, these studies reveal a plausible PT scheme consisting of Y1394, D1507, and a conserved crystallographic water molecule, with all components of the scheme being stable during the MD simulation and the energy barrier low for PT to occur. The two-dimensional potential energy surface for the nucleophilic attack process was also calculated. The comparison of potential energies for two possible elimination half-reaction mechanisms revealed that Y1467 reprotonates the coenzyme-A leaving group to form product. This study provides new insights into the detailed catalytic mechanism of p300 and has important implications for the discovery of novel small molecule regulators for p300.
authors: Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University , Xi'an 710032, China.
authors: Xinlei
authors: X
authors: Zhang
authors: Sisheng
authors: S
authors: Ouyang
authors: Xiangqian
authors: X
authors: Kong
authors: Zhongjie
authors: Z
authors: Liang
authors: Junyan
authors: J
authors: Lu
authors: Kongkai
authors: K
authors: Zhu
authors: Dan
authors: D
authors: Zhao
authors: Mingyue
authors: M
authors: Zheng
authors: Hualiang
authors: H
authors: Jiang
authors: Xin
authors: X
authors: Liu
authors: Ronen
authors: R
authors: Marmorstein
authors: Cheng
authors: C
authors: Luo
mesh_terms: D000105:Acetyl Coenzyme A / Q000737:chemistry / Q000378:metabolism; D000107:Acetylation; D055162:Biocatalysis; D051548:Histone Acetyltransferases / Q000737:chemistry* / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D011522:Protons
chemical_list: D006657:Histones; D011522:Protons; D000105:Acetyl Coenzyme A; D051548:Histone Acetyltransferases