6Y6S

Mouse Galactocerebrosidase complexed with galacto-noeurostegine GNS at pH 6.8

PDB DOI: https://doi.org/10.2210/pdb6Y6S/pdb

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

Deposited: 2020-02-27 Released: 2021-01-13
Deposition Author(s): Deane, J.E., McLoughlin, J.
Funding Organization(s): Royal Society

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.201
R-Value Work: 0.163
R-Value Observed: 0.165

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

The Bicyclic Form of galacto -Noeurostegine Is a Potent Inhibitor of beta-Galactocerebrosidase.

Viuff, A., Salamone, S., McLoughlin, J., Deane, J.E., Jensen, H.H.

(2021) ACS Med Chem Lett 12: 56-59

PubMed: 33488964 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.0c00377
Primary Citation of Related Structures:
6Y6S, 6Y6T

PubMed Abstract:
Competitive inhibitors of galactocerebrosidase (GALC) could be candidates for pharmacological chaperone therapy of patients with Krabbe disease. The known and selective nortropane-type iminosugar galacto -noeurostegine has been found to competitively inhibit GALC with K _i = 7 μM at pH 4.6, which is 330-fold more potent than the analogous deoxynoeurostegine. It was shown through X-ray protein crystallography that galacto -noeurostegine binds to the active site of GALC in its bicyclic form.

Organizational Affiliation

Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark.

Macromolecule Content

Total Structure Weight: 76.38 kDa
Atom Count: 5,506
Modelled Residue Count: 641
Deposited Residue Count: 654
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Galactocerebrosidase	A	654	Mus musculus	Mutation(s): 0 Gene Names: Galc EC: 3.2.1.46
UniProt
Find proteins for P54818 (Mus musculus) Explore P54818 Go to UniProtKB: P54818
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P54818
Glycosylation
Glycosylation Sites: 4	Glycosylation Focus chain A	Go to GlyGen: P54818-1
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)-2-acetamido-2-deoxy-beta-D-glucopyranose	B, C, D	2		N-Glycosylation	Interactions Focus chain B Focus chain C Focus chain D Interactions & Density Focus chain B Focus chain C Focus chain D
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]
ODW (Subject of Investigation/LOI) Query on ODW Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	(1~{R},2~{S},3~{S},4~{R},5~{R})-4-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-1,2,3-triol C₈ H₁₅ N O₄ NLSPHUUFXPUPJJ-GWVFRZDISA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
NI Query on NI 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]	NICKEL (II) ION Ni VEQPNABPJHWNSG-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Interactions & Density Focus chain H [auth A]
CA Query on CA 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]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
ODW	BindingDB: 6Y6S	Ki: 7000 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.201
R-Value Work: 0.163
R-Value Observed: 0.165
Space Group: H 3 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 248.721	α = 90
b = 248.721	β = 90
c = 77.326	γ = 120

Software Package:

Software Name	Purpose
PHENIX	refinement
PHENIX	refinement
DIALS	data reduction
DIALS	data scaling
PHENIX	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2021-01-13

Deposition Author(s):

Deane, J.E.

McLoughlin, J.

Funding Organization	Location	Grant Number
Royal Society	United Kingdom	UF100371

Revision History (Full details and data files)

Version 1.0: 2021-01-13
Type: Initial release
Version 1.1: 2021-02-03
Changes: Database references
Version 1.2: 2024-01-24
Changes: Data collection, Database references, Refinement description
Version 1.3: 2024-10-16
Changes: Structure summary