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Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?

[Image: see text] Fe(II)-dependent oxygenases employ hydrogen atom transfer (HAT) to produce a myriad of products. Understanding how such enzymes use dynamic processes beyond the immediate vicinity of the active site to control the selectivity and efficiency of HAT is important for metalloenzyme eng...

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Autores principales: Chaturvedi, Shobhit S., Jaber Sathik Rifayee, Simahudeen Bathir, Waheed, Sodiq O., Wildey, Jon, Warner, Cait, Schofield, Christopher J., Karabencheva-Christova, Tatyana G., Christov, Christo Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516565/
https://www.ncbi.nlm.nih.gov/pubmed/36186565
http://dx.doi.org/10.1021/jacsau.2c00345
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author Chaturvedi, Shobhit S.
Jaber Sathik Rifayee, Simahudeen Bathir
Waheed, Sodiq O.
Wildey, Jon
Warner, Cait
Schofield, Christopher J.
Karabencheva-Christova, Tatyana G.
Christov, Christo Z.
author_facet Chaturvedi, Shobhit S.
Jaber Sathik Rifayee, Simahudeen Bathir
Waheed, Sodiq O.
Wildey, Jon
Warner, Cait
Schofield, Christopher J.
Karabencheva-Christova, Tatyana G.
Christov, Christo Z.
author_sort Chaturvedi, Shobhit S.
collection PubMed
description [Image: see text] Fe(II)-dependent oxygenases employ hydrogen atom transfer (HAT) to produce a myriad of products. Understanding how such enzymes use dynamic processes beyond the immediate vicinity of the active site to control the selectivity and efficiency of HAT is important for metalloenzyme engineering; however, obtaining such knowledge by experiments is challenging. This study develops a computational framework for identifying second coordination sphere (SCS) and especially long-range (LR) residues relevant for catalysis through dynamic cross-correlation analysis (DCCA) using the human histone demethylase PHF8 (KDM7B) as a model oxygenase. Furthermore, the study explores the mechanistic pathways of influence of the SCS and LR residues on the HAT reaction. To demonstrate the plausibility of the approach, we investigated the effect of a PHF8 F279S clinical mutation associated with X-linked intellectual disability, which has been experimentally shown to ablate PHF8-catalyzed demethylation. In agreement, the molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) studies showed a change in the H3(1–14)K9me2 substrate orientation and an increased HAT barrier. We systematically analyzed the pathways by which the identified SCS and LR residues may influence HAT by exploring changes in H3K9me2 substrate orientation, interdomain correlated motions, HAT transition state stabilization, reaction energetics, electron transfer mechanism, and alterations in the intrinsic electric field of PHF8. Importantly, SCS and LR variations decrease key motions of α9−α12 of the JmjC domain toward the Fe(IV)-center that are associated with tighter binding of the H3(1–14)K9me2 substrate. SCS and LR residues alter the intrinsic electric field of the enzyme along the reaction coordinate and change the individual energetic contributions of residues toward TS stabilization. The overall results suggest that DCCA can indeed identify non-active-site residues relevant for catalysis. The substitutions of such dynamically correlated residues might be used as a tool to tune HAT in non-heme Fe(II)- and 2OG-dependent enzymes.
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spelling pubmed-95165652022-09-29 Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase? Chaturvedi, Shobhit S. Jaber Sathik Rifayee, Simahudeen Bathir Waheed, Sodiq O. Wildey, Jon Warner, Cait Schofield, Christopher J. Karabencheva-Christova, Tatyana G. Christov, Christo Z. JACS Au [Image: see text] Fe(II)-dependent oxygenases employ hydrogen atom transfer (HAT) to produce a myriad of products. Understanding how such enzymes use dynamic processes beyond the immediate vicinity of the active site to control the selectivity and efficiency of HAT is important for metalloenzyme engineering; however, obtaining such knowledge by experiments is challenging. This study develops a computational framework for identifying second coordination sphere (SCS) and especially long-range (LR) residues relevant for catalysis through dynamic cross-correlation analysis (DCCA) using the human histone demethylase PHF8 (KDM7B) as a model oxygenase. Furthermore, the study explores the mechanistic pathways of influence of the SCS and LR residues on the HAT reaction. To demonstrate the plausibility of the approach, we investigated the effect of a PHF8 F279S clinical mutation associated with X-linked intellectual disability, which has been experimentally shown to ablate PHF8-catalyzed demethylation. In agreement, the molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) studies showed a change in the H3(1–14)K9me2 substrate orientation and an increased HAT barrier. We systematically analyzed the pathways by which the identified SCS and LR residues may influence HAT by exploring changes in H3K9me2 substrate orientation, interdomain correlated motions, HAT transition state stabilization, reaction energetics, electron transfer mechanism, and alterations in the intrinsic electric field of PHF8. Importantly, SCS and LR variations decrease key motions of α9−α12 of the JmjC domain toward the Fe(IV)-center that are associated with tighter binding of the H3(1–14)K9me2 substrate. SCS and LR residues alter the intrinsic electric field of the enzyme along the reaction coordinate and change the individual energetic contributions of residues toward TS stabilization. The overall results suggest that DCCA can indeed identify non-active-site residues relevant for catalysis. The substitutions of such dynamically correlated residues might be used as a tool to tune HAT in non-heme Fe(II)- and 2OG-dependent enzymes. American Chemical Society 2022-08-18 /pmc/articles/PMC9516565/ /pubmed/36186565 http://dx.doi.org/10.1021/jacsau.2c00345 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Chaturvedi, Shobhit S.
Jaber Sathik Rifayee, Simahudeen Bathir
Waheed, Sodiq O.
Wildey, Jon
Warner, Cait
Schofield, Christopher J.
Karabencheva-Christova, Tatyana G.
Christov, Christo Z.
Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?
title Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?
title_full Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?
title_fullStr Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?
title_full_unstemmed Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?
title_short Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?
title_sort can second coordination sphere and long-range interactions modulate hydrogen atom transfer in a non-heme fe(ii)-dependent histone demethylase?
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516565/
https://www.ncbi.nlm.nih.gov/pubmed/36186565
http://dx.doi.org/10.1021/jacsau.2c00345
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