9I03 | pdb_00009i03

Structure of recombinant human butyrylcholinesterase in complex with (R)-N-((1-benzylpyrrolidin-3-yl)methyl)-N-methylnaphthalene-2-sulfonamide

PDB DOI: https://doi.org/10.2210/pdb9I03/pdb

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

Deposited: 2025-01-14 Released: 2025-07-02
Deposition Author(s): Brazzolotto, X., Kosak, U., Gobec, S., Nachon, F.
Funding Organization(s): French Ministry of Armed Forces

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.56 Å
R-Value Free:
0.238 (Depositor), 0.235 (DCC)
R-Value Work:
0.185 (Depositor), 0.186 (DCC)
R-Value Observed:
0.188 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.0 of the entry. See complete history.

Literature

Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease.

Kosak, U., Strasek Benedik, N., Knez, D., Zakelj, S., Trontelj, J., Pislar, A., Horvat, S., Bolje, A., Znidarsic, N., Grgurevic, N., Svara, T., Kljun, J., Skrzypczak-Wiercioch, A., Lv, B., Xiong, Y., Wang, Q., Bian, R., Shao, J., Dias, J., Nachon, F., Brazzolotto, X., Stojan, J., Sun, H., Salat, K., Gobec, S.

(2025) J Med Chem 68: 11693-11723

PubMed: 40454648 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.5c00577
Primary Citation of Related Structures:
9I02, 9I03

PubMed Abstract:
Butyrylcholinesterase (BChE) is a promising drug target for alleviating the symptoms of canine cognitive dysfunction (CCD) and Alzheimer's disease (AD). We have recently developed lead compound 2 , a racemic, nanomolar BChE inhibitor with procognitive effects in mice with scopolamine-induced AD-like symptoms and dogs suffering from CCD. To overcome its modest brain exposure, we developed compound ( R )-(-)-3 , a more potent BChE inhibitor with a 7-fold higher in vivo brain exposure. It has procognitive effects in mice with scopolamine-induced AD-like symptoms and, superior to compound 2 , also in mice with Aβ _1-42-induced AD-like symptoms. Compound ( R )-(-)-3 produces no cholinergic adverse effects or motor deficits and has no acute toxic effects in mice. This makes sulfonamide ( R )-(-)-3 an optimized lead compound for alleviating the symptoms of AD.

Organizational Affiliation

Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.

Macromolecule Content

Total Structure Weight: 64.26 kDa
Atom Count: 4,635
Modeled Residue Count: 526
Deposited Residue Count: 529
Unique protein chains: 1

Macromolecules

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(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
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose	B, C	3		N-Glycosylation	Interactions Focus chain B Focus chain C Interactions & Density Focus chain B Focus chain C

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

Entity ID: 4
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose	E	5		N-Glycosylation	Interactions Focus chain E Interactions & Density Focus chain E

Small Molecules

Ligands 8 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1IYQ (Subject of Investigation/LOI) Query on A1IYQ 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}-methyl-~{N}-[[(3~{R})-1-(phenylmethyl)pyrrolidin-3-yl]methyl]naphthalene-2-sulfonamide C₂₃ H₂₆ N₂ O₂ S FNPKLEUPADIGIY-UHFFFAOYSA-N		Interactions Focus chain M [auth A] Interactions & Density Focus chain M [auth A]
SIA Query on SIA 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]	N-acetyl-alpha-neuraminic acid C₁₁ H₁₉ N O₉ SQVRNKJHWKZAKO-YRMXFSIDSA-N		Interactions Focus chain L [auth A] Interactions & Density Focus chain L [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 I [auth A] MOL2 format, chain I [auth A] mmCIF format, chain I [auth A]	I [auth A]	2-(N-MORPHOLINO)-ETHANESULFONIC ACID C₆ H₁₃ N O₄ S SXGZJKUKBWWHRA-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain O [auth A] SDF format, chain P [auth A] SDF format, chain Q [auth A] SDF format, chain R [auth A] MOL2 format, chain O [auth A] MOL2 format, chain P [auth A] MOL2 format, chain Q [auth A] MOL2 format, chain R [auth A] mmCIF format, chain O [auth A] mmCIF format, chain P [auth A] mmCIF format, chain Q [auth A] mmCIF format, chain R [auth A]	O [auth A], P [auth A], Q [auth A], R [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain O [auth A] Focus chain P [auth A] Focus chain Q [auth A] Focus chain R [auth A] Interactions & Density Focus chain O [auth A] Focus chain P [auth A] Focus chain Q [auth A] Focus chain R [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] MOL2 format, chain H [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] mmCIF format, chain H [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A]	H [auth A], J [auth A], K [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain J [auth A] Focus chain K [auth A] Interactions & Density Focus chain H [auth A] Focus chain J [auth A] Focus chain K [auth A]
PPI Query on PPI 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]	PROPANOIC ACID C₃ H₆ O₂ XBDQKXXYIPTUBI-UHFFFAOYSA-N		Interactions Focus chain N [auth A] Interactions & Density Focus chain N [auth A]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain S [auth A] SDF format, chain T [auth A] MOL2 format, chain S [auth A] MOL2 format, chain T [auth A] mmCIF format, chain S [auth A] mmCIF format, chain T [auth A]	S [auth A], T [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain S [auth A] Focus chain T [auth A] Interactions & Density Focus chain S [auth A] Focus chain T [auth A]