7QB4

Mus Musculus Acetylcholinesterase in complex with 7-[(1-benzylpiperidin-3-yl)methoxy]-3,4-dimethyl-2H-chromen-2-one

PDB DOI: https://doi.org/10.2210/pdb7QB4/pdb

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

Deposited: 2021-11-18 Released: 2022-04-06
Deposition Author(s): Ekstrom, F.J., Forsgren, N.
Funding Organization(s): Other government

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.50 Å
R-Value Free: 0.217
R-Value Work: 0.184
R-Value Observed: 0.185

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

This is version 1.2 of the entry. See complete history.

Literature

Dual Reversible Coumarin Inhibitors Mutually Bound to Monoamine Oxidase B and Acetylcholinesterase Crystal Structures.

Ekstrom, F., Gottinger, A., Forsgren, N., Catto, M., Iacovino, L.G., Pisani, L., Binda, C.

(2022) ACS Med Chem Lett 13: 499-506

PubMed: 35300078 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.2c00001
Primary Citation of Related Structures:
7P4F, 7P4H, 7QAK, 7QB4

PubMed Abstract:
Multitarget directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies. The synergistic inhibition of monoamine oxidase B (MAO B) and acetylcholinesterase (AChE) is believed to provide a potentiated effect in the treatment of Alzheimer's disease. Among previously reported micromolar or sub-micromolar coumarin-bearing dual inhibitors, compound 1 returned a tight-binding inhibition of MAO B ( K _i = 4.5 μM) and a +5.5 °C increase in the enzyme T _m value. Indeed, the X-ray crystal structure revealed that binding of 1 produces unforeseen conformational changes at the MAO B entrance cavity. Interestingly, 1 showed great shape complementarity with the AChE enzymatic gorge, being deeply buried from the catalytic anionic subsite (CAS) to the peripheral anionic subsite (PAS) and causing significant structural changes in the active site. These findings provide structural templates for further development of dual MAO B and AChE inhibitors.

Organizational Affiliation

Swedish Defence Research Agency, CBRN Defence and Security, Umeå 901 82, Sweden.

Macromolecule Content

Total Structure Weight: 123.44 kDa
Atom Count: 8,754
Modelled Residue Count: 1,072
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 Focus chain B	Go to GlyGen: P21836-1
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
AJ9 (Subject of Investigation/LOI) Query on AJ9 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain R [auth B] MOL2 format, chain E [auth A] MOL2 format, chain R [auth B] mmCIF format, chain E [auth A] mmCIF format, chain R [auth B]	E [auth A], R [auth B]	3,4-dimethyl-7-[[1-(phenylmethyl)piperidin-4-yl]methoxy]chromen-2-one C₂₄ H₂₇ N O₃ MWFBGTXYOJLQIW-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain R [auth B] Interactions & Density Focus chain E [auth A] Focus chain R [auth B]
9YU Query on 9YU Download Ideal Coordinates CCD File SDF format, chain AA [auth B] MOL2 format, chain AA [auth B] mmCIF format, chain AA [auth B]	AA [auth B]	2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol C₁₅ H₃₂ O₈ AGWKUHGLWHMYTG-UHFFFAOYSA-N		Interactions Focus chain AA [auth B] Interactions & Density Focus chain AA [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain Q [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain Q [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain Q [auth B]	C [auth A], D [auth A], Q [auth B]	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] Focus chain Q [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain Q [auth B]
TOE Query on TOE Download Ideal Coordinates CCD File SDF format, chain Z [auth B] MOL2 format, chain Z [auth B] mmCIF format, chain Z [auth B]	Z [auth B]	2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXYL C₇ H₁₆ O₄ JLGLQAWTXXGVEM-UHFFFAOYSA-N		Interactions Focus chain Z [auth B] Interactions & Density Focus chain Z [auth B]
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 L [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain O [auth A] SDF format, chain P [auth A] SDF format, chain V [auth B] SDF format, chain W [auth B] SDF format, chain X [auth B] SDF format, chain Y [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 L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain O [auth A] MOL2 format, chain P [auth A] MOL2 format, chain V [auth B] MOL2 format, chain W [auth B] MOL2 format, chain X [auth B] MOL2 format, chain Y [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 L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain O [auth A] mmCIF format, chain P [auth A] mmCIF format, chain V [auth B] mmCIF format, chain W [auth B] mmCIF format, chain X [auth B] mmCIF format, chain Y [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], L [auth A], M [auth A], N [auth A], O [auth A], P [auth A], V [auth B], W [auth B], X [auth B], Y [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 L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain P [auth A] Focus chain V [auth B] Focus chain W [auth B] Focus chain X [auth B] Focus chain Y [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 L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain P [auth A] Focus chain V [auth B] Focus chain W [auth B] Focus chain X [auth B] Focus chain Y [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain U [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain U [auth B]	S [auth B], T [auth B], U [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Interactions & Density Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B]