A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies

Gerlits, Oksana O.; Ho, Kwok -Yiu; Cheng, Xiaolin; Blumenthal, Donald; Taylor, Palmer; Kovalevsky, Andrey; Radić, Zoran

doi:10.1016/j.cbi.2019.06.011

Title: A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies

Abstract

Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P3₁ and a new unit cell, amenable for room-temperature X-ray diffraction studies. Here, we co-crystallized hAChE in P3₁ unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P3₁ space group structures appear similar to those previously obtained in the different P3₁21 unit cell. Successful solution of the new room temperature 3.2 Å resolution structure of BW284c51*hAChE complex from large P3₁ crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature-relatedmore »« less

Authors:

^[1]; Ho, Kwok -Yiu ^[2]; Cheng, Xiaolin ^[3]; Blumenthal, Donald ^[4]; Taylor, Palmer ^[2]; Kovalevsky, Andrey ^[5]; Radić, Zoran ^[2]

Univ. of Tennessee, Knoxville, TN (United States)
Univ. of California San Diego, La Jolla, CA (United States)
The Ohio State Univ., Columbus, OH (United States)
Univ. of Utah, Salt Lake City, UT (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Publication Date:: Fri Jun 07 00:00:00 EDT 2019

Research Org.:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Org.:: USDOE

OSTI Identifier:: 1559608

Alternate Identifier(s):: OSTI ID: 1529996

Grant/Contract Number:: AC05-00OR22725

Resource Type:: Accepted Manuscript

Journal Name:: Chemico-Biological Interactions

Additional Journal Information:: Journal Volume: 309; Journal Issue: C; Journal ID: ISSN 0009-2797

Publisher:: Elsevier

Country of Publication:: United States

Language:: English

Subject:: 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; Human acetylcholinesterase; Room-temperature X-ray structure; Structure-based drug design; Donepezil; 9-Aminoacridine; BW284c51

Citation Formats


                    Gerlits, Oksana O., Ho, Kwok -Yiu, Cheng, Xiaolin, Blumenthal, Donald, Taylor, Palmer, Kovalevsky, Andrey, and Radić, Zoran. A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies.  United States: N. p., 2019. 
Web.  doi:10.1016/j.cbi.2019.06.011.

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                    Gerlits, Oksana O., Ho, Kwok -Yiu, Cheng, Xiaolin, Blumenthal, Donald, Taylor, Palmer, Kovalevsky, Andrey, & Radić, Zoran. A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies.  United States.  https://doi.org/10.1016/j.cbi.2019.06.011

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                    Gerlits, Oksana O., Ho, Kwok -Yiu, Cheng, Xiaolin, Blumenthal, Donald, Taylor, Palmer, Kovalevsky, Andrey, and Radić, Zoran. Fri .  
"A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies".  United States.  https://doi.org/10.1016/j.cbi.2019.06.011.  https://www.osti.gov/servlets/purl/1559608.

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@article{osti_1559608,

  title        = {A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies},

  author       = {Gerlits, Oksana O. and Ho, Kwok -Yiu and Cheng, Xiaolin and Blumenthal, Donald and Taylor, Palmer and Kovalevsky, Andrey and Radić, Zoran},

  abstractNote = {Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P31 and a new unit cell, amenable for room-temperature X-ray diffraction studies. Here, we co-crystallized hAChE in P31 unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P31 space group structures appear similar to those previously obtained in the different P3121 unit cell. Successful solution of the new room temperature 3.2 Å resolution structure of BW284c51*hAChE complex from large P31 crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature-related conformational diversity could be expected in both oxime and hAChE, which could lead to better informed structure-based design under conditions approaching physiological temperature.},

  doi          = {10.1016/j.cbi.2019.06.011},

  journal      = {Chemico-Biological Interactions},

  number       = C,

  volume       = 309,

  place        = {United States},

  year         = {Fri Jun 07 00:00:00 EDT 2019},

  month        = {Fri Jun 07 00:00:00 EDT 2019}

}

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Works referencing / citing this record:

Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones
journal, December 2019

Rullo, Mariagrazia; Catto, Marco; Carrieri, Antonio
Molecules, Vol. 24, Issue 24
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Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory Potential of Phthalimide‐Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease
journal, October 2019

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Chemistry & Biodiversity, Vol. 16, Issue 11
DOI: 10.1002/cbdv.201900370

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DOI: 10.3390/molecules24244507

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Similar Records

Title: A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies

Abstract

Citation Formats

Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence journal, January 1986

Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein journal, August 1991

Structure of acetylcholinesterase complexed with E2020 (Aricept®): implications for the design of new anti-Alzheimer drugs journal, March 1999

The impact of crystallization conditions on structure-based drug design: A case study on the methylene blue/acetylcholinesterase complex: The Impact of Crystallization Conditions on Structure-Based Drug Design journal, March 2016

Oxime-assisted Acetylcholinesterase Catalytic Scavengers of Organophosphates That Resist Aging journal, July 2011

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes journal, July 2006

Structures of Human Acetylcholinesterase in Complex with Pharmacologically Important Ligands journal, October 2012

PHENIX: a comprehensive Python-based system for macromolecular structure solution journal, January 2010

MolProbity: all-atom contacts and structure validation for proteins and nucleic acids journal, May 2007

Features and development of Coot journal, March 2010

Inference of Macromolecular Assemblies from Crystalline State journal, September 2007

Three distinct domains in the cholinesterase molecule confer selectivity for acetyl- and butyrylcholinesterase inhibitors journal, November 1993

Interaction Kinetics of Reversible Inhibitors and Substrates with Acetylcholinesterase and Its Fasciculin 2 Complex journal, February 2001

Donepezil: An Important Prototype to the Design of New Drug Candidates for Alzheimer’s Disease journal, January 2014

Biochemical and Histochemical Comparison of Cholinesterases in Normal and Alzheimer Brain Tissues journal, August 2010

Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. journal, October 1993

Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase journal, July 2013

Structure of a complex of the potent and specific inhibitor BW284C51 with Torpedo californica acetylcholinesterase journal, September 2002

Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones journal, December 2019

Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory Potential of Phthalimide‐Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease journal, October 2019

Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones journal, December 2019

Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence
journal, January 1986

Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein
journal, August 1991

Structure of acetylcholinesterase complexed with E2020 (Aricept®): implications for the design of new anti-Alzheimer drugs
journal, March 1999

The impact of crystallization conditions on structure-based drug design: A case study on the methylene blue/acetylcholinesterase complex: The Impact of Crystallization Conditions on Structure-Based Drug Design
journal, March 2016

Oxime-assisted Acetylcholinesterase Catalytic Scavengers of Organophosphates That Resist Aging
journal, July 2011

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes
journal, July 2006

Structures of Human Acetylcholinesterase in Complex with Pharmacologically Important Ligands
journal, October 2012

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

MolProbity: all-atom contacts and structure validation for proteins and nucleic acids
journal, May 2007

Features and development of Coot
journal, March 2010

Inference of Macromolecular Assemblies from Crystalline State
journal, September 2007

Three distinct domains in the cholinesterase molecule confer selectivity for acetyl- and butyrylcholinesterase inhibitors
journal, November 1993

Interaction Kinetics of Reversible Inhibitors and Substrates with Acetylcholinesterase and Its Fasciculin 2 Complex
journal, February 2001

Donepezil: An Important Prototype to the Design of New Drug Candidates for Alzheimer’s Disease
journal, January 2014

Biochemical and Histochemical Comparison of Cholinesterases in Normal and Alzheimer Brain Tissues
journal, August 2010

Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase.
journal, October 1993

Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase
journal, July 2013

Structure of a complex of the potent and specific inhibitor BW284C51 with Torpedo californica acetylcholinesterase
journal, September 2002

Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones
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