6NEA

Human Acetylcholinesterase in complex with reactivator, HLo7

PDB DOI: https://doi.org/10.2210/pdb6NEA/pdb

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

Deposited: 2018-12-17 Released: 2019-06-12
Deposition Author(s): Bester, S.M., McGuire, J., Height, J.J., Pegan, S.D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.42 ?
R-Value Free: 0.205
R-Value Work: 0.176
R-Value Observed: 0.177

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.2 of the entry. See complete history.

Literature

Synthesis and Molecular Properties of Nerve Agent Reactivator HLo-7 Dimethanesulfonate.

Hsu, F.L., Bae, S.Y., McGuire, J., Anderson, D.R., Bester, S.M., Height, J.J., Pegan, S.D., Walz, A.J.

(2019) ACS Med Chem Lett 10: 761-766

PubMed: 31097996 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.9b00021
Primary Citation of Related Structures:
6NEA

PubMed Abstract:
The threat of a deliberate release of chemical nerve agents has underscored the need to continually improve field effective treatments for these types of poisonings. The oxime containing HL?-7 is a potential second-generation therapeutic reactivator. A synthetic process for HL?-7 is detailed with improvements to the DIBAL reduction and ion exchange steps. HL?-7 was visualized for the first time within the active site of human acetylcholinesterase and its relative ex vivo potency confirmed against various nerve agents using a phrenic nerve hemidiaphragm assay.

Organizational Affiliation

United States Army Edgewood Chemical Biological Center, Aberdeen Proving Ground, Maryland 21010, United States.

Macromolecule Content

Total Structure Weight: 121.75 kDa
Atom Count: 9,103
Modelled Residue Count: 1,061
Deposited Residue Count: 1,084
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	542	Homo sapiens	Mutation(s): 0 Gene Names: ACHE EC: 3.1.1.7
UniProt & NIH Common Fund Data Resources
Find proteins for P22303 (Homo sapiens) Explore P22303 Go to UniProtKB: P22303
PHAROS: P22303 GTEx: ENSG00000087085
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P22303
Glycosylation
Glycosylation Sites: 2	Glycosylation Focus chain A Focus chain B	Go to GlyGen: P22303-1
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose	C, D	3		N-Glycosylation	Interactions Focus chain C Focus chain D Interactions & Density Focus chain C Focus chain D
Glycosylation Resources
GlyTouCan: G21290RB GlyCosmos: G21290RB GlyGen: G21290RB

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
HLO Query on HLO Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain K [auth B] MOL2 format, chain F [auth A] MOL2 format, chain K [auth B] mmCIF format, chain F [auth A] mmCIF format, chain K [auth B]	F [auth A], K [auth B]	1-[({2,4-BIS[(E)-(HYDROXYIMINO)METHYL]PYRIDINIUM-1-YL}METHOXY)METHYL]-4-CARBAMOYLPYRIDINIUM C₁₅ H₁₇ N₅ O₄ SODKCPHRJDOHMI-UHFFFAOYSA-P		Interactions Focus chain F [auth A] Focus chain K [auth B] Interactions & Density Focus chain F [auth A] Focus chain K [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth A] SDF format, chain J [auth B] SDF format, chain I [auth A] MOL2 format, chain E [auth A] MOL2 format, chain H [auth A] MOL2 format, chain J [auth B] MOL2 format, chain I [auth A] mmCIF format, chain E [auth A] mmCIF format, chain H [auth A] mmCIF format, chain J [auth B] mmCIF format, chain I [auth A]	E [auth A], H [auth A], I [auth A], J [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain E [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth B] Interactions & Density Focus chain E [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth B]
FUC Query on FUC Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A] mmCIF format, chain G [auth A]	G [auth A]	alpha-L-fucopyranose C₆ H₁₂ O₅ SHZGCJCMOBCMKK-SXUWKVJYSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.42 ?
R-Value Free: 0.205
R-Value Work: 0.176
R-Value Observed: 0.177
Space Group: P 3₁ 2 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 104.73	α = 90
b = 104.73	β = 90
c = 324.247	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
HKL-2000	data reduction
HKL-2000	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2019-06-12

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2019-06-12
Type: Initial release
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2023-10-11
Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary
Version 2.2: 2024-10-23
Changes: Structure summary