6QAA

Human Butyrylcholinesterase in complex with (S)-2-(butylamino)-N-(2-cycloheptylethyl)-3-(1H-indol-3-yl)propanamide

PDB DOI: https://doi.org/10.2210/pdb6QAA/pdb

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

Deposited: 2018-12-19 Released: 2019-03-27
Deposition Author(s): Brazzolotto, X., Nachon, F., Harst, M., Knez, D., Gobec, S.
Funding Organization(s): French Ministry of Armed Forces

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.208
R-Value Work: 0.176
R-Value Observed: 0.178

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.1 of the entry. See complete history.

Literature

Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease.

Meden, A., Knez, D., Jukic, M., Brazzolotto, X., Grsic, M., Pislar, A., Zahirovic, A., Kos, J., Nachon, F., Svete, J., Gobec, S., Groselj, U.

(2019) Chem Commun (Camb) 55: 3765-3768

PubMed: 30864579 Search on PubMed
DOI: https://doi.org/10.1039/c9cc01330j
Primary Citation of Related Structures:
6QAA, 6QAB, 6QAC, 6QAD, 6QAE

PubMed Abstract:
We have identified tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors. They are defined according to their chemical modularity, novel binding mode revealed by five solved crystal structures with human BChE, low cytotoxicity, and predicted permeability of the blood-brain barrier. Altogether, these factors indicate their potential as unique lead compounds for symptomatic therapy against Alzheimer's disease.

Organizational Affiliation

Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia. uros.groselj@fkkt.uni-lj.si.

Macromolecule Content

Total Structure Weight: 66.69 kDa
Atom Count: 4,757
Modelled Residue Count: 526
Deposited Residue Count: 557
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	557	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
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

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	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 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
HUN (Subject of Investigation/LOI) Query on HUN Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A]	I [auth A]	butyl-[(2~{S})-1-(2-cycloheptylethylamino)-3-(1~{H}-indol-3-yl)-1-oxidanylidene-propan-2-yl]azanium C₂₄ H₃₈ N₃ O LDOSYPMIOHKIEJ-QHCPKHFHSA-O		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A]	E [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 E [auth A] Focus chain F [auth A] Focus chain G [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A]
MES Query on MES Download Ideal Coordinates CCD File SDF format, chain O [auth A] MOL2 format, chain O [auth A]	O [auth A]	2-(N-MORPHOLINO)-ETHANESULFONIC ACID C₆ H₁₃ N O₄ S SXGZJKUKBWWHRA-UHFFFAOYSA-N		Interactions Focus chain O [auth A] Interactions & Density Focus chain O [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain P [auth A] SDF format, chain Q [auth A] SDF format, chain R [auth A] SDF format, chain S [auth A] MOL2 format, chain P [auth A] MOL2 format, chain Q [auth A] MOL2 format, chain R [auth A] MOL2 format, chain S [auth A]	P [auth A], Q [auth A], R [auth A], S [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain P [auth A] Focus chain Q [auth A] Focus chain R [auth A] Focus chain S [auth A] Interactions & Density Focus chain P [auth A] Focus chain Q [auth A] Focus chain R [auth A] Focus chain S [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain J [auth A] SDF format, chain M [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain J [auth A] MOL2 format, chain M [auth A]	J [auth A], K [auth A], L [auth A], M [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Interactions & Density Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain N [auth A] MOL2 format, chain H [auth A] MOL2 format, chain N [auth A]	H [auth A], N [auth A]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain N [auth A] Interactions & Density Focus chain H [auth A] Focus chain N [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
HUN	Binding MOAD: 6QAA	IC50: 22 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.208
R-Value Work: 0.176
R-Value Observed: 0.178
Space Group: I 4 2 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 154.597	α = 90
b = 154.597	β = 90
c = 128.214	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
Coot	model building
XDS	data reduction
XDS	data scaling
PHENIX	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2019-03-27

Deposition Author(s):

Funding Organization	Location	Grant Number
French Ministry of Armed Forces	France	PDH-2-NRBC-3-C-3201

Revision History (Full details and data files)

Version 1.0: 2019-03-27
Type: Initial release
Version 1.1: 2019-04-03
Changes: Data collection, Database references
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2024-01-24
Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary