4PEE

Crystal structure of a bacterial fucosidase with inhibitor 1-phenyl-4-[(2S,3S,4R,5S)-3,4-dihydroxy-5-methylpyrrolidin-2-yl]triazole

PDB DOI: https://doi.org/10.2210/pdb4PEE/pdb

Classification: HYDROLASE
Organism(s): Bacteroides thetaiotaomicron VPI-5482
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2014-04-23 Released: 2014-07-09
Deposition Author(s): Wright, D.W., Davies, G.J., Behr, J.B.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.95 Å
R-Value Free: 0.229
R-Value Work: 0.191
R-Value Observed: 0.193

Starting Model: experimental
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Ligand Structure Quality Assessment

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

Literature

Exploiting the Hydrophobic Terrain in Fucosidases with Aryl-Substituted Pyrrolidine Iminosugars.

Hottin, A., Wright, D.W., Davies, G.J., Behr, J.B.

(2015) Chembiochem 16: 277-283

PubMed: 25427942 Search on PubMed
DOI: https://doi.org/10.1002/cbic.201402509
Primary Citation of Related Structures:
4PCS, 4PCT, 4PEE

PubMed Abstract:
Fucosidase inhibition shows potential in numerous therapeutic contexts. Substitution of fucose-like iminosugars with hydrophobic "aglycons" yields significant improvements in potency of fucosidase inhibition. Here we have prepared three new 2-aryl-3,4-dihydroxy-5-methylpyrrolidines featuring phenyl substituents in variable orientations with respect to the iminocyclitol core and at various distances from it to explore the key binding interactions that stabilise the enzyme-inhibitor complex. The presence of a triazole linker in one structure resulted in nanomolar inhibition of the fucosidase from bovine kidney (Ki =4.8 nM), thus giving rise to one of the most potent pyrrolidine-type inhibitors of this enzyme known to date.

Organizational Affiliation

Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, UFR des Sciences Exactes et Naturelles, 51687 Reims Cedex 2 (France).

Macromolecule Content

Total Structure Weight: 209.07 kDa
Atom Count: 15,332
Modelled Residue Count: 1,782
Deposited Residue Count: 1,788
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Alpha-L-fucosidase	A, B, C, D	447	Bacteroides thetaiotaomicron VPI-5482	Mutation(s): 0 Gene Names: BT_2970
UniProt
Find proteins for Q8A3I4 (Bacteroides thetaiotaomicron (strain ATCC 29148 / DSM 2079 / JCM 5827 / CCUG 10774 / NCTC 10582 / VPI-5482 / E50)) Explore Q8A3I4 Go to UniProtKB: Q8A3I4
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q8A3I4
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
2OX Query on 2OX Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain L [auth B] SDF format, chain P [auth C] SDF format, chain T [auth D] MOL2 format, chain H [auth A] MOL2 format, chain L [auth B] MOL2 format, chain P [auth C] MOL2 format, chain T [auth D] mmCIF format, chain H [auth A] mmCIF format, chain L [auth B] mmCIF format, chain P [auth C] mmCIF format, chain T [auth D]	H [auth A], L [auth B], P [auth C], T [auth D]	(2S,3R,4S,5S)-2-methyl-5-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrrolidine-3,4-diol C₁₃ H₁₆ N₄ O₂ HPPFSIKUULBMIZ-KNDHEWATSA-N		Interactions Focus chain H [auth A] Focus chain L [auth B] Focus chain P [auth C] Focus chain T [auth D] Interactions & Density Focus chain H [auth A] Focus chain L [auth B] Focus chain P [auth C] Focus chain T [auth D]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain M [auth C] SDF format, chain Q [auth D] SDF format, chain E [auth A] SDF format, chain N [auth C] MOL2 format, chain F [auth A] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain M [auth C] MOL2 format, chain Q [auth D] MOL2 format, chain E [auth A] MOL2 format, chain N [auth C] mmCIF format, chain F [auth A] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain M [auth C] mmCIF format, chain Q [auth D] mmCIF format, chain E [auth A] mmCIF format, chain N [auth C]	E [auth A] F [auth A] I [auth B] J [auth B] M [auth C] E [auth A], F [auth A], I [auth B], J [auth B], M [auth C], N [auth C], Q [auth D]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain M [auth C] Focus chain N [auth C] Focus chain Q [auth D] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain M [auth C] Focus chain N [auth C] Focus chain Q [auth D]
IMD Query on IMD Download Ideal Coordinates CCD File SDF format, chain K [auth B] SDF format, chain G [auth A] SDF format, chain O [auth C] SDF format, chain R [auth D] SDF format, chain S [auth D] MOL2 format, chain K [auth B] MOL2 format, chain G [auth A] MOL2 format, chain O [auth C] MOL2 format, chain R [auth D] MOL2 format, chain S [auth D] mmCIF format, chain K [auth B] mmCIF format, chain G [auth A] mmCIF format, chain O [auth C] mmCIF format, chain R [auth D] mmCIF format, chain S [auth D]	G [auth A], K [auth B], O [auth C], R [auth D], S [auth D]	IMIDAZOLE C₃ H₅ N₂ RAXXELZNTBOGNW-UHFFFAOYSA-O		Interactions Focus chain G [auth A] Focus chain K [auth B] Focus chain O [auth C] Focus chain R [auth D] Focus chain S [auth D] Interactions & Density Focus chain G [auth A] Focus chain K [auth B] Focus chain O [auth C] Focus chain R [auth D] Focus chain S [auth D]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.95 Å
R-Value Free: 0.229
R-Value Work: 0.191
R-Value Observed: 0.193
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 56.04	α = 90
b = 187.59	β = 94.26
c = 97.7	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
Aimless	data scaling
PDB_EXTRACT	data extraction

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-07-09

Deposition Author(s):

Wright, D.W.

Davies, G.J.

Behr, J.B.

Revision History (Full details and data files)

Version 1.0: 2014-07-09
Type: Initial release
Version 1.1: 2014-12-10
Changes: Database references
Version 1.2: 2015-01-21
Changes: Database references
Version 1.3: 2023-12-20
Changes: Data collection, Database references, Refinement description

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Help and Resources

4PEE

Crystal structure of a bacterial fucosidase with inhibitor 1-phenyl-4-[(2S,3S,4R,5S)-3,4-dihydroxy-5-methylpyrrolidin-2-yl]triazole

Exploiting the Hydrophobic Terrain in Fucosidases with Aryl-Substituted Pyrrolidine Iminosugars.

Entity ID: 1

UniProt

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)