7R2F

Structure of tabun inhibited acetylcholinesterase in complex with 2-((hydroxyimino)methyl)-1-(5-(4-methyl-3-nitrobenzamido)pentyl)pyridinium

PDB DOI: https://doi.org/10.2210/pdb7R2F/pdb

Classification: HYDROLASE
Organism(s): Mus musculus
Expression System: Homo sapiens
Mutation(s): No

Deposited: 2022-02-04 Released: 2022-04-27
Deposition Author(s): Forsgren, N., Lindgren, C., Edvinsson, L., Linusson, A., Ekstrom, F.
Funding Organization(s): Other government, Swedish Research Council

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.30 ?
R-Value Free: 0.205
R-Value Work: 0.172
R-Value Observed: 0.173

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase.

Lindgren, C., Forsgren, N., Hoster, N., Akfur, C., Artursson, E., Edvinsson, L., Svensson, R., Worek, F., Ekstrom, F., Linusson, A.

(2022) Chemistry 28: e202200678-e202200678

PubMed: 35420233 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/chem.202200678
Primary Citation of Related Structures:
7QYN, 7R02, 7R0A, 7R2F, 7R3C, 7R4E

PubMed Abstract:
Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.

Organizational Affiliation

Department of Chemistry, Ume? University, 901 87, Ume?, Sweden.

Macromolecule Content

Total Structure Weight: 123.05 kDa
Atom Count: 9,476
Modelled Residue Count: 1,069
Deposited Residue Count: 1,086
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Acetylcholinesterase	A, B	543	Mus musculus	Mutation(s): 0 Gene Names: Ache EC: 3.1.1.7
UniProt & NIH Common Fund Data Resources
Find proteins for P21836 (Mus musculus) Explore P21836 Go to UniProtKB: P21836
IMPC: MGI:87876
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P21836
Glycosylation
Glycosylation Sites: 2	Glycosylation Focus chain A	Go to GlyGen: P21836-1
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
7PG Query on 7PG Download Ideal Coordinates CCD File SDF format, chain U [auth B] MOL2 format, chain U [auth B] mmCIF format, chain U [auth B]	U [auth B]	2,5,8,11,14,17,20,23-OCTAOXAPENTACOSAN-25-OL C₁₇ H₃₆ O₉ SZGNWRSFHADOMY-UHFFFAOYSA-N		Interactions Focus chain U [auth B] Interactions & Density Focus chain U [auth B]
I1X (Subject of Investigation/LOI) Query on I1X Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain L [auth B] MOL2 format, chain E [auth A] MOL2 format, chain L [auth B] mmCIF format, chain E [auth A] mmCIF format, chain L [auth B]	E [auth A], L [auth B]	4-methyl-3-nitro-~{N}-[(2~{E},4~{E})-5-[2-[(oxidanylamino)methyl]pyridin-1-yl]penta-2,4-dienyl]benzamide C₁₉ H₂₃ N₄ O₄ GLQZXKLUIAIZJA-UHFFFAOYSA-O		Interactions Focus chain E [auth A] Focus chain L [auth B] Interactions & Density Focus chain E [auth A] Focus chain L [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A]	C [auth A], D [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A]
PG0 Query on PG0 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B]	F [auth A] G [auth A] H [auth A] I [auth A] J [auth A] F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], M [auth B], N [auth B], O [auth B], P [auth B], Q [auth B], R [auth B], S [auth B], T [auth B]	2-(2-METHOXYETHOXY)ETHANOL C₅ H₁₂ O₃ SBASXUCJHJRPEV-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B]