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Article ; Online: Structural and dynamic effects of paraoxon binding to human acetylcholinesterase by X-ray crystallography and inelastic neutron scattering.

Gerlits, Oksana / Fajer, Mikolai / Cheng, Xiaolin / Blumenthal, Donald K / Radić, Zoran / Kovalevsky, Andrey

Structure (London, England : 1993)

2022 Volume 30, Issue 11, Page(s) 1538–1549.e3

Abstract: Organophosphorus (OP) compounds, including nerve agents and some pesticides, covalently bind to the catalytic serine of human acetylcholinesterase (hAChE), thereby inhibiting acetylcholine hydrolysis necessary for efficient neurotransmission. Oxime ... ...

Abstract	Organophosphorus (OP) compounds, including nerve agents and some pesticides, covalently bind to the catalytic serine of human acetylcholinesterase (hAChE), thereby inhibiting acetylcholine hydrolysis necessary for efficient neurotransmission. Oxime antidotes can reactivate the OP-conjugated hAChE, but reactivation efficiency can be low for pesticides, such as paraoxon (POX). Understanding structural and dynamic determinants of OP inhibition and reactivation can provide insights to design improved reactivators. Here, X-ray structures of hAChE with unaged POX, with POX and oximes MMB4 and RS170B, and with MMB4 are reported. A significant conformational distortion of the acyl loop was observed upon POX binding, being partially restored to the native conformation by oximes. Neutron vibrational spectroscopy combined with molecular dynamics simulations showed that picosecond vibrational dynamics of the acyl loop soften in the ∼20-50 cm
MeSH term(s)	Humans ; Acetylcholinesterase/chemistry ; Paraoxon/chemistry ; Crystallography, X-Ray ; Cholinesterase Inhibitors/chemistry ; Oximes/chemistry ; Organophosphorus Compounds ; Neutrons ; Pesticides
Chemical Substances	Acetylcholinesterase (EC 3.1.1.7) ; Paraoxon (Q9CX8P80JW) ; Cholinesterase Inhibitors ; Oximes ; Organophosphorus Compounds ; Pesticides
Language	English
Publishing date	2022-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2022.09.006
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Article ; Online: Revealing protonation states and tracking substrate in serine hydroxymethyltransferase with room-temperature X-ray and neutron crystallography.

Drago, Victoria N / Campos, Claudia / Hooper, Mattea / Collins, Aliyah / Gerlits, Oksana / Weiss, Kevin L / Blakeley, Matthew P / Phillips, Robert S / Kovalevsky, Andrey

Communications chemistry

2023 Volume 6, Issue 1, Page(s) 162

Abstract: Pyridoxal 5'-phosphate (PLP)-dependent enzymes utilize a vitamin ... ...

Abstract	Pyridoxal 5'-phosphate (PLP)-dependent enzymes utilize a vitamin B
Language	English
Publishing date	2023-08-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2929562-2
ISSN	2399-3669 ; 2399-3669
ISSN (online)	2399-3669
ISSN	2399-3669
DOI	10.1038/s42004-023-00964-9
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Article ; Online: Room temperature crystallography of human acetylcholinesterase bound to a substrate analogue 4K-TMA: Towards a neutron structure.

Gerlits, Oksana / Blakeley, Matthew P / Keen, David A / Radić, Zoran / Kovalevsky, Andrey

Current research in structural biology

2021 Volume 3, Page(s) 206–215

Abstract: Acetylcholinesterase (AChE) catalyzes hydrolysis of acetylcholine thereby terminating cholinergic nerve impulses for efficient neurotransmission. Human AChE (hAChE) is a target of nerve agent and pesticide organophosphorus compounds that covalently ... ...

Abstract	Acetylcholinesterase (AChE) catalyzes hydrolysis of acetylcholine thereby terminating cholinergic nerve impulses for efficient neurotransmission. Human AChE (hAChE) is a target of nerve agent and pesticide organophosphorus compounds that covalently attach to the catalytic Ser203 residue. Reactivation of inhibited hAChE can be achieved with nucleophilic antidotes, such as oximes. Understanding structural and electrostatic (i.e. protonation states) determinants of the catalytic and reactivation processes is crucial to improve design of oxime reactivators. Here we report X-ray structures of hAChE conjugated with a reversible covalent inhibitor 4K-TMA (4K-TMA:hAChE) at 2.8 Å resolution and of 4K-TMA:hAChE conjugate with oxime reactivator methoxime, MMB4 (4K-TMA:hAChE:MMB4) at 2.6 Å resolution, both at physiologically relevant room temperature, as well as cryo-crystallographic structure of 4K-TMA:hAChE at 2.4 Å resolution. 4K-TMA acts as a substrate analogue reacting with the hydroxyl of Ser203 and generating a reversible tetrahedral hemiketal intermediate that closely resembles the first tetrahedral intermediate state during hAChE-catalyzed acetylcholine hydrolysis. Structural comparisons of room temperature with cryo-crystallographic structures of 4K-TMA:hAChE and published mAChE complexes with 4K-TMA, as well as the effect of MMB4 binding to the peripheral anionic site (PAS) of the 4K-TMA:hAChE complex, revealed only discrete, minor differences. The active center geometry of AChE, already highly evolved for the efficient catalysis, was thus indicative of only minor conformational adjustments to accommodate the tetrahedral intermediate in the hydrolysis of the neurotransmitter acetylcholine (ACh). To map protonation states in the hAChE active site gorge we collected 3.5 Å neutron diffraction data paving the way for obtaining higher resolution datasets that will be needed to determine locations of individual hydrogen atoms.
Language	English
Publishing date	2021-09-06
Publishing country	Netherlands
Document type	Journal Article
ISSN	2665-928X
ISSN (online)	2665-928X
DOI	10.1016/j.crstbi.2021.08.003
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Article ; Online: Joint neutron/molecular dynamics vibrational spectroscopy reveals softening of HIV-1 protease upon binding of a tight inhibitor.

Kneller, Daniel W / Gerlits, Oksana / Daemen, Luke L / Pavlova, Anna / Gumbart, James C / Cheng, Yongqiang / Kovalevsky, Andrey

Physical chemistry chemical physics : PCCP

2022 Volume 24, Issue 6, Page(s) 3586–3597

Abstract: Biomacromolecules are inherently dynamic, and their dynamics are interwoven into function. The fast collective vibrational dynamics in proteins occurs in the low picosecond timescale corresponding to frequencies of ∼5-50 ... ...

Abstract	Biomacromolecules are inherently dynamic, and their dynamics are interwoven into function. The fast collective vibrational dynamics in proteins occurs in the low picosecond timescale corresponding to frequencies of ∼5-50 cm
MeSH term(s)	HIV Protease/chemistry ; HIV-1/enzymology ; Molecular Dynamics Simulation ; Neutrons ; Spectrum Analysis ; Vibration
Chemical Substances	HIV Protease (EC 3.4.23.-) ; p16 protease, Human immunodeficiency virus 1 (EC 3.4.23.-)
Language	English
Publishing date	2022-02-09
Publishing country	England
Document type	Journal Article
ZDB-ID	1476244-4
ISSN	1463-9084 ; 1463-9076
ISSN (online)	1463-9084
ISSN	1463-9076
DOI	10.1039/d1cp05487b
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Article ; Online: Protein kinase A in the neutron beam: Insights for catalysis from directly observing protons.

Gerlits, Oksana / Weiss, Kevin L / Blakeley, Matthew P / Veglia, Gianluigi / Taylor, Susan S / Kovalevsky, Andrey

Methods in enzymology

2020 Volume 634, Page(s) 311–331

Abstract: Protein kinases transmit chemical signals by phosphorylating substrate proteins, thus regulating a multitude of cellular processes. cAMP-dependent protein kinase (PKA), a prototypical enzyme for the whole kinase family, has been the focus of research for ...

Abstract	Protein kinases transmit chemical signals by phosphorylating substrate proteins, thus regulating a multitude of cellular processes. cAMP-dependent protein kinase (PKA), a prototypical enzyme for the whole kinase family, has been the focus of research for several decades, however, the details of the chemical mechanism of phosphoryl group transfer have remained unknown. We used neutron crystallography to map key proton sites and hydrogen bonding interactions in the PKA catalytic subunit (PKAc) in a product complex containing adenosine diphosphate (ADP) and the phosphorylated high affinity protein kinase substrate (pPKS) peptide. To improve neutron diffraction, we deuterated PKAc allowing us to use very small crystals. In the product complex, the phosphoryl group of pPKS is protonated whereas the catalytic Asp166 is not. H/D exchange analysis of the main-chain amides and comparison with the NMR analysis of PKAc with inhibitor peptide complex revealed exchangeable amides that may distinguish the catalytic and inhibited states.
MeSH term(s)	Catalysis ; Cyclic AMP-Dependent Protein Kinases ; Models, Molecular ; Neutrons ; Protons
Chemical Substances	Protons ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
Language	English
Publishing date	2020-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2019.12.003
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Article ; Online: Zooming in on protons: Neutron structure of protein kinase A trapped in a product complex.

Gerlits, Oksana / Weiss, Kevin L / Blakeley, Matthew P / Veglia, Gianluigi / Taylor, Susan S / Kovalevsky, Andrey

Science advances

2019 Volume 5, Issue 3, Page(s) eaav0482

Abstract: The question vis-à-vis the chemistry of phosphoryl group transfer catalyzed by protein kinases remains a major challenge. The neutron diffraction structure of the catalytic subunit of cAMP-dependent protein kinase (PKA-C) provides a more complete ... ...

Abstract	The question vis-à-vis the chemistry of phosphoryl group transfer catalyzed by protein kinases remains a major challenge. The neutron diffraction structure of the catalytic subunit of cAMP-dependent protein kinase (PKA-C) provides a more complete chemical portrait of key proton interactions at the active site. By using a high-affinity protein kinase substrate (PKS) peptide, we captured the reaction products, dephosphorylated nucleotide [adenosine diphosphate (ADP)] and phosphorylated PKS (pPKS), bound at the active site. In the complex, the phosphoryl group of the peptide is protonated, whereas the carboxyl group of the catalytic Asp
MeSH term(s)	Adenosine Diphosphate/chemistry ; Amides/chemistry ; Amino Acid Sequence ; Animals ; Binding Sites ; Catalysis ; Catalytic Domain/genetics ; Crystallography, X-Ray ; Cyclic AMP-Dependent Protein Kinases/chemistry ; Magnetic Resonance Spectroscopy ; Mice ; Models, Molecular ; Neutrons ; Nucleotides/chemistry ; Peptides/chemistry ; Phosphorylation ; Protein Conformation ; Protein Kinase C/chemistry ; Protons ; Substrate Specificity ; Water/chemistry
Chemical Substances	Amides ; Nucleotides ; Peptides ; Protons ; Water (059QF0KO0R) ; Adenosine Diphosphate (61D2G4IYVH) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2019-03-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.aav0482
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Article: Neutron Crystallography Detects Differences in Protein Dynamics: Structure of the PKG II Cyclic Nucleotide Binding Domain in Complex with an Activator

Gerlits, Oksana / Campbell, James C / Blakeley, Matthew P / Kim, Choel / Kovalevsky, Andrey

Biochemistry. 2018 Mar. 08, v. 57, no. 12

2018

Abstract: As one of the main receptors of a second messenger, cGMP, cGMP-dependent protein kinase (PKG) isoforms I and II regulate distinct physiological processes. The design of isoform-specific activators is thus of great biomedical importance and requires ... ...

Abstract	As one of the main receptors of a second messenger, cGMP, cGMP-dependent protein kinase (PKG) isoforms I and II regulate distinct physiological processes. The design of isoform-specific activators is thus of great biomedical importance and requires detailed structural information about PKG isoforms bound with activators, including accurate positions of hydrogen atoms and a description of the hydrogen bonding and water architecture. Here, we determined a 2.2 Å room-temperature joint X-ray/neutron (XN) structure of the human PKG II carboxyl cyclic nucleotide binding (CNB-B) domain bound with a potent PKG II activator, 8-pCPT-cGMP. The XN structure directly visualizes intermolecular interactions and reveals changes in hydrogen bonding patterns upon comparison to the X-ray structure determined at cryo-temperatures. Comparative analysis of the backbone hydrogen/deuterium exchange patterns in PKG II:8-pCPT-cGMP and previously reported PKG Iβ:cGMP XN structures suggests that the ability of these agonists to activate PKG is related to how effectively they quench dynamics of the cyclic nucleotide binding pocket and the surrounding regions.
Keywords	X-radiation ; agonists ; ambient temperature ; cGMP-dependent protein kinase ; crystallography ; cyclic GMP ; deuterium ; humans ; hydrogen bonding ; neutrons ; receptors ; second messengers
Language	English
Dates of publication	2018-0308
Size	p. 1833-1837.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.8b00010
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 217: Show issues

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Article ; Online: Mannobiose Binding Induces Changes in Hydrogen Bonding and Protonation States of Acidic Residues in Concanavalin A As Revealed by Neutron Crystallography.

Gerlits, Oksana O / Coates, Leighton / Woods, Robert J / Kovalevsky, Andrey

Biochemistry

2017 Volume 56, Issue 36, Page(s) 4747–4750

Abstract: Plant lectins are carbohydrate-binding proteins with various biomedical applications. Concanavalin A (Con A) holds promise in treating cancerous tumors. To better understand the Con A carbohydrate binding specificity, we obtained a room-temperature ... ...

Abstract	Plant lectins are carbohydrate-binding proteins with various biomedical applications. Concanavalin A (Con A) holds promise in treating cancerous tumors. To better understand the Con A carbohydrate binding specificity, we obtained a room-temperature neutron structure of this legume lectin in complex with a disaccharide Manα1-2Man, mannobiose. The neutron structure afforded direct visualization of the hydrogen bonding between the protein and ligand, showing that the ligand is able to alter both protonation states and interactions for residues located close to and distant from the binding site. An unprecedented low-barrier hydrogen bond was observed forming between the carboxylic side chains of Asp28 and Glu8, with the D atom positioned equidistant from the oxygen atoms having an O···D···O angle of 101.5°.
MeSH term(s)	Amino Acid Sequence ; Binding Sites ; Concanavalin A/chemistry ; Concanavalin A/metabolism ; Hydrogen Bonding ; Mannans/chemistry ; Mannans/metabolism ; Protein Conformation
Chemical Substances	Mannans ; Concanavalin A (11028-71-0) ; mannobiose (15548-43-3)
Language	English
Publishing date	2017-09-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.7b00654
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Article: An N⋯H⋯N low-barrier hydrogen bond preorganizes the catalytic site of aspartate aminotransferase to facilitate the second half-reaction.

Drago, Victoria N / Dajnowicz, Steven / Parks, Jerry M / Blakeley, Matthew P / Keen, David A / Coquelle, Nicolas / Weiss, Kevin L / Gerlits, Oksana / Kovalevsky, Andrey / Mueser, Timothy C

Chemical science

2022 Volume 13, Issue 34, Page(s) 10057–10065

Abstract: Pyridoxal 5'-phosphate (PLP)-dependent enzymes have been extensively studied for their ability to fine-tune PLP cofactor electronics to promote a wide array of chemistries. Neutron crystallography offers a straightforward approach to studying the ... ...

Abstract	Pyridoxal 5'-phosphate (PLP)-dependent enzymes have been extensively studied for their ability to fine-tune PLP cofactor electronics to promote a wide array of chemistries. Neutron crystallography offers a straightforward approach to studying the electronic states of PLP and the electrostatics of enzyme active sites, responsible for the reaction specificities, by enabling direct visualization of hydrogen atom positions. Here we report a room-temperature joint X-ray/neutron structure of aspartate aminotransferase (AAT) with pyridoxamine 5'-phosphate (PMP), the cofactor product of the first half reaction catalyzed by the enzyme. Between PMP N
Language	English
Publishing date	2022-08-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d2sc02285k
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Article ; Online: Substrate Binding Stiffens Aspartate Aminotransferase by Altering the Enzyme Picosecond Vibrational Dynamics.

Dajnowicz, Steven / Cheng, Yongqiang / Daemen, Luke L / Weiss, Kevin L / Gerlits, Oksana / Mueser, Timothy C / Kovalevsky, Andrey

ACS omega

2020 Volume 5, Issue 30, Page(s) 18787–18797

Abstract: Protein dynamics on various time scales from femtoseconds to milliseconds impacts biological function by driving proteins to conformations conducive to ligand binding and creating functional states in enzyme catalysis. Neutron vibrational spectroscopy ... ...

Abstract	Protein dynamics on various time scales from femtoseconds to milliseconds impacts biological function by driving proteins to conformations conducive to ligand binding and creating functional states in enzyme catalysis. Neutron vibrational spectroscopy carried out by measuring inelastic neutron scattering from protein molecules in combination with molecular simulations has the unique ability of detecting and visualizing changes in the picosecond protein vibrational dynamics due to ligand binding. Here we present neutron vibrational spectra of a homodimeric pyridoxal 5'-phosphate-dependent enzyme, aspartate aminotransferase, obtained from the open internal aldimine and closed external aldimine conformational states. We observe that in the external aldimine state the protein structure stiffens relative to the internal aldimine state, indicating rigidified vibrational dynamics on the picosecond time scale in the low-frequency regime of 5-50 cm
Language	English
Publishing date	2020-07-23
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.0c01900
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