9EWU | pdb_00009ewu

Crystal structure of human butyrylcholinesterase in complex with (2R,3S)-1-[(cyclopropylmethyl)amino]-3-[(9H-fluoren-9-yl)amino]-4-phenylbutan-2-ol

PDB DOI: https://doi.org/10.2210/pdb9EWU/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Cricetulus griseus
Mutation(s): Yes

Deposited: 2024-04-04 Released: 2025-02-05
Deposition Author(s): Panek, D., Pasieka, A., Malawska, B., Nachon, F., Brazzolotto, X.
Funding Organization(s): French Ministry of Armed Forces

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.45 Å
R-Value Free:
0.244 (Depositor), 0.248 (DCC)
R-Value Work:
0.188 (Depositor), 0.188 (DCC)
R-Value Observed:
0.191 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease.

Panek, D., Pasieka, A., Jonczyk, J., Gawlinska, M., Zareba, P., Siwek, A., Wolak, M., Mordyl, B., Gluch-Lutwin, M., Latacz, G., Brazzolotto, X., Chantegreil, F., Nachon, F., Zdarova Karasova, J., Pejchal, J., Mzik, M., Sestak, V., Prchal, L., Odvarkova, J., Soukup, O., Korabecny, J., Sorf, A., Hamsikova, M., Zemanova, L., Muckova, L., Vanova, N., Dryja, P., Salat, K., Hofner, G., Wanner, K., Wieckowska, A., Malawska, B.

(2025) Angew Chem Int Ed Engl 64: e202420510-e202420510

PubMed: 39523866 Search on PubMed
DOI: https://doi.org/10.1002/anie.202420510
Primary Citation of Related Structures:
9EWU

PubMed Abstract:
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as γ-aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, using a combination of crystallography and computational methods we developed compound 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC ₅₀=0.21 μM) and GABA transporter 1 (IC ₅₀=10.96 μM) and 3 (IC ₅₀=7.76 μM), along with a favorable drug-likeness profile. Subsequent in vivo studies revealed the effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi-target-directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD.

Organizational Affiliation

Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna St. 9, 30-688, Cracow, Poland.

Macromolecule Content

Total Structure Weight: 63.52 kDa
Atom Count: 4,587
Modelled Residue Count: 526
Deposited Residue Count: 529
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Cholinesterase	A	529	Homo sapiens	Mutation(s): 4 Gene Names: BCHE, CHE1 EC: 3.1.1.8
UniProt & NIH Common Fund Data Resources
Find proteins for P06276 (Homo sapiens) Explore P06276 Go to UniProtKB: P06276
PHAROS: P06276 GTEx: ENSG00000114200
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P06276
Glycosylation
Glycosylation Sites: 6	Glycosylation Focus chain A	Go to GlyGen: P06276-1
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose	B	2		N-Glycosylation	Interactions Focus chain B Interactions & Density Focus chain B
Glycosylation Resources
GlyTouCan: G86851RC GlyCosmos: G86851RC GlyGen: G86851RC

Entity ID: 3
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, E	3		N-Glycosylation	Interactions Focus chain C Focus chain D Focus chain E Interactions & Density Focus chain C Focus chain D Focus chain E
Glycosylation Resources
GlyTouCan: G21290RB GlyCosmos: G21290RB GlyGen: G21290RB

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1H77 (Subject of Investigation/LOI) Query on A1H77 Download Ideal Coordinates CCD File SDF format, chain N [auth A] MOL2 format, chain N [auth A] mmCIF format, chain N [auth A]	N [auth A]	(2~{R},3~{S})-1-(cyclopropylmethylamino)-3-(9~{H}-fluoren-9-ylamino)-4-phenyl-butan-2-ol C₂₇ H₃₀ N₂ O UUSOVXKDONMOKG-UHFFFAOYSA-N		Interactions Focus chain N [auth A] Interactions & Density Focus chain N [auth A]
SIA Query on SIA Download Ideal Coordinates CCD File SDF format, chain M [auth A] MOL2 format, chain M [auth A] mmCIF format, chain M [auth A]	M [auth A]	N-acetyl-alpha-neuraminic acid C₁₁ H₁₉ N O₉ SQVRNKJHWKZAKO-YRMXFSIDSA-N		Interactions Focus chain M [auth A] Interactions & Density Focus chain M [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A]	F [auth A], G [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Interactions & Density Focus chain F [auth A] Focus chain G [auth A]
MES Query on MES Download Ideal Coordinates CCD File SDF format, chain H [auth A] MOL2 format, chain H [auth A] mmCIF format, chain H [auth A]	H [auth A]	2-(N-MORPHOLINO)-ETHANESULFONIC ACID C₆ H₁₃ N O₄ S SXGZJKUKBWWHRA-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Interactions & Density Focus chain H [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A]	I [auth A], J [auth A], K [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Interactions & Density Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain L [auth A] MOL2 format, chain L [auth A] mmCIF format, chain L [auth A]	L [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain L [auth A] Interactions & Density Focus chain L [auth A]