6MOZ

Structure of acid-beta-glucosidase in complex with an aromatic pyrrolidine iminosugar inhibitor

PDB DOI: https://doi.org/10.2210/pdb6MOZ/pdb

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

Deposited: 2018-10-05 Released: 2019-06-19
Deposition Author(s): Patterson-Orazem, A.C., Lieberman, R.L.
Funding Organization(s): National Institutes of Health/National Eye Institute (NIH/NEI)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.228
R-Value Work: 0.200
R-Value Observed: 0.201

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Exploring substituent diversity on pyrrolidine-aryltriazole iminosugars: Structural basis of beta-glucocerebrosidase inhibition.

Martinez-Bailen, M., Carmona, A.T., Patterson-Orazem, A.C., Lieberman, R.L., Ide, D., Kubo, M., Kato, A., Robina, I., Moreno-Vargas, A.J.

(2019) Bioorg Chem 86: 652-664

PubMed: 30825709 Search on PubMed
DOI: https://doi.org/10.1016/j.bioorg.2019.02.025
Primary Citation of Related Structures:
6MOZ

PubMed Abstract:
The synthesis of a library of pyrrolidine-aryltriazole hybrids through CuAAC between two epimeric dihydroxylated azidomethylpyrrolidines and differently substituted phenylacetylenes is reported. The evaluation of the new compounds as inhibitors of lysosomal β-glucocerebrosidase showed the importance of the substitution pattern of the phenyl moiety in the inhibition. Crystallization and docking studies revealed key interactions of the pyrrolidine motif with aminoacid residues of the catalytic site while the aryltriazole moiety extended along a hydrophobic surface groove. Some of these compounds were able to increase the enzyme activity in Gaucher patient fibroblasts, acting as a new type of chemical chaperone for Gaucher disease.

Organizational Affiliation

Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Prof. García González, 1, 41012-Seville, Spain.

Macromolecule Content

Total Structure Weight: 113.45 kDa
Atom Count: 8,118
Modelled Residue Count: 994
Deposited Residue Count: 994
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Glucosylceramidase	A, B	497	Homo sapiens	Mutation(s): 1 Gene Names: GBA, GC, GLUC EC: 3.2.1.45 (PDB Primary Data), 3.2.1.46 (UniProt), 2.4.1 (UniProt), 3.2.1 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P04062 (Homo sapiens) Explore P04062 Go to UniProtKB: P04062
PHAROS: P04062 GTEx: ENSG00000177628
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P04062
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain A Focus chain B	Go to GlyGen: P04062-1
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
JXA (Subject of Investigation/LOI) Query on JXA Download Ideal Coordinates CCD File SDF format, chain S [auth A] MOL2 format, chain S [auth A] mmCIF format, chain S [auth A]	S [auth A]	(2R,3S,4R)-2-{[4-(3,5-dichlorophenyl)-1H-1,2,3-triazol-1-yl]methyl}pyrrolidine-3,4-diol C₁₃ H₁₄ Cl₂ N₄ O₂ QVWPLFTVMWIDFF-UPJWGTAASA-N		Interactions Focus chain S [auth A] Interactions & Density Focus chain S [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain W [auth B] MOL2 format, chain C [auth A] MOL2 format, chain W [auth B] mmCIF format, chain C [auth A] mmCIF format, chain W [auth B]	C [auth A], W [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain C [auth A] Focus chain W [auth B] Interactions & Density Focus chain C [auth A] Focus chain W [auth B]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain PA [auth B] SDF format, chain QA [auth B] SDF format, chain RA [auth B] SDF format, chain T [auth A] SDF format, chain U [auth A] SDF format, chain V [auth A] MOL2 format, chain PA [auth B] MOL2 format, chain QA [auth B] MOL2 format, chain RA [auth B] MOL2 format, chain T [auth A] MOL2 format, chain U [auth A] MOL2 format, chain V [auth A] mmCIF format, chain PA [auth B] mmCIF format, chain QA [auth B] mmCIF format, chain RA [auth B] mmCIF format, chain T [auth A] mmCIF format, chain U [auth A] mmCIF format, chain V [auth A]	PA [auth B] QA [auth B] RA [auth B] T [auth A] U [auth A] PA [auth B], QA [auth B], RA [auth B], T [auth A], U [auth A], V [auth A]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain PA [auth B] Focus chain QA [auth B] Focus chain RA [auth B] Focus chain T [auth A] Focus chain U [auth A] Focus chain V [auth A] Interactions & Density Focus chain PA [auth B] Focus chain QA [auth B] Focus chain RA [auth B] Focus chain T [auth A] Focus chain U [auth A] Focus chain V [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain OA [auth B] MOL2 format, chain OA [auth B] mmCIF format, chain OA [auth B]	OA [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain OA [auth B] Interactions & Density Focus chain OA [auth B]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain AA [auth B] SDF format, chain BA [auth B] SDF format, chain CA [auth B] SDF format, chain D [auth A] SDF format, chain DA [auth B] SDF format, chain E [auth A] SDF format, chain EA [auth B] SDF format, chain F [auth A] SDF format, chain FA [auth B] SDF format, chain G [auth A] SDF format, chain GA [auth B] SDF format, chain H [auth A] SDF format, chain HA [auth B] SDF format, chain I [auth A] SDF format, chain IA [auth B] SDF format, chain J [auth A] SDF format, chain JA [auth B] SDF format, chain K [auth A] SDF format, chain KA [auth B] SDF format, chain L [auth A] SDF format, chain LA [auth B] SDF format, chain M [auth A] SDF format, chain MA [auth B] SDF format, chain N [auth A] SDF format, chain NA [auth B] SDF format, chain O [auth A] SDF format, chain P [auth A] SDF format, chain Q [auth A] SDF format, chain R [auth A] SDF format, chain X [auth B] SDF format, chain Y [auth B] SDF format, chain Z [auth B] MOL2 format, chain AA [auth B] MOL2 format, chain BA [auth B] MOL2 format, chain CA [auth B] MOL2 format, chain D [auth A] MOL2 format, chain DA [auth B] MOL2 format, chain E [auth A] MOL2 format, chain EA [auth B] MOL2 format, chain F [auth A] MOL2 format, chain FA [auth B] MOL2 format, chain G [auth A] MOL2 format, chain GA [auth B] MOL2 format, chain H [auth A] MOL2 format, chain HA [auth B] MOL2 format, chain I [auth A] MOL2 format, chain IA [auth B] MOL2 format, chain J [auth A] MOL2 format, chain JA [auth B] MOL2 format, chain K [auth A] MOL2 format, chain KA [auth B] MOL2 format, chain L [auth A] MOL2 format, chain LA [auth B] MOL2 format, chain M [auth A] MOL2 format, chain MA [auth B] MOL2 format, chain N [auth A] MOL2 format, chain NA [auth B] MOL2 format, chain O [auth A] MOL2 format, chain P [auth A] MOL2 format, chain Q [auth A] MOL2 format, chain R [auth A] MOL2 format, chain X [auth B] MOL2 format, chain Y [auth B] MOL2 format, chain Z [auth B] mmCIF format, chain AA [auth B] mmCIF format, chain BA [auth B] mmCIF format, chain CA [auth B] mmCIF format, chain D [auth A] mmCIF format, chain DA [auth B] mmCIF format, chain E [auth A] mmCIF format, chain EA [auth B] mmCIF format, chain F [auth A] mmCIF format, chain FA [auth B] mmCIF format, chain G [auth A] mmCIF format, chain GA [auth B] mmCIF format, chain H [auth A] mmCIF format, chain HA [auth B] mmCIF format, chain I [auth A] mmCIF format, chain IA [auth B] mmCIF format, chain J [auth A] mmCIF format, chain JA [auth B] mmCIF format, chain K [auth A] mmCIF format, chain KA [auth B] mmCIF format, chain L [auth A] mmCIF format, chain LA [auth B] mmCIF format, chain M [auth A] mmCIF format, chain MA [auth B] mmCIF format, chain N [auth A] mmCIF format, chain NA [auth B] mmCIF format, chain O [auth A] mmCIF format, chain P [auth A] mmCIF format, chain Q [auth A] mmCIF format, chain R [auth A] mmCIF format, chain X [auth B] mmCIF format, chain Y [auth B] mmCIF format, chain Z [auth B]	AA [auth B] BA [auth B] CA [auth B] D [auth A] DA [auth B] AA [auth B], BA [auth B], CA [auth B], D [auth A], DA [auth B], E [auth A], EA [auth B], F [auth A], FA [auth B], G [auth A], GA [auth B], H [auth A], HA [auth B], I [auth A], IA [auth B], J [auth A], JA [auth B], K [auth A], KA [auth B], L [auth A], LA [auth B], M [auth A], MA [auth B], N [auth A], NA [auth B], O [auth A], P [auth A], Q [auth A], R [auth A], X [auth B], Y [auth B], Z [auth B]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain AA [auth B] Focus chain BA [auth B] Focus chain CA [auth B] Focus chain D [auth A] Focus chain DA [auth B] Focus chain E [auth A] Focus chain EA [auth B] Focus chain F [auth A] Focus chain FA [auth B] Focus chain G [auth A] Focus chain GA [auth B] Focus chain H [auth A] Focus chain HA [auth B] Focus chain I [auth A] Focus chain IA [auth B] Focus chain J [auth A] Focus chain JA [auth B] Focus chain K [auth A] Focus chain KA [auth B] Focus chain L [auth A] Focus chain LA [auth B] Focus chain M [auth A] Focus chain MA [auth B] Focus chain N [auth A] Focus chain NA [auth B] Focus chain O [auth A] Focus chain P [auth A] Focus chain Q [auth A] Focus chain R [auth A] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B] Interactions & Density Focus chain AA [auth B] Focus chain BA [auth B] Focus chain CA [auth B] Focus chain D [auth A] Focus chain DA [auth B] Focus chain E [auth A] Focus chain EA [auth B] Focus chain F [auth A] Focus chain FA [auth B] Focus chain G [auth A] Focus chain GA [auth B] Focus chain H [auth A] Focus chain HA [auth B] Focus chain I [auth A] Focus chain IA [auth B] Focus chain J [auth A] Focus chain JA [auth B] Focus chain K [auth A] Focus chain KA [auth B] Focus chain L [auth A] Focus chain LA [auth B] Focus chain M [auth A] Focus chain MA [auth B] Focus chain N [auth A] Focus chain NA [auth B] Focus chain O [auth A] Focus chain P [auth A] Focus chain Q [auth A] Focus chain R [auth A] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.228
R-Value Work: 0.200
R-Value Observed: 0.201
Space Group: C 2 2 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 110.28	α = 90
b = 285.01	β = 90
c = 91.68	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
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: 2019-06-19

Deposition Author(s):

Patterson-Orazem, A.C.

Lieberman, R.L.

Funding Organization	Location	Grant Number
National Institutes of Health/National Eye Institute (NIH/NEI)	United States	021205

Revision History (Full details and data files)

Version 1.0: 2019-06-19
Type: Initial release
Version 1.1: 2019-12-11
Changes: Author supporting evidence
Version 1.2: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Data collection, Derived calculations, Structure summary
Version 1.3: 2023-10-11
Changes: Data collection, Database references, Refinement description, Structure summary
Version 1.4: 2024-11-13
Changes: Structure summary