3DDF

GOLGI MANNOSIDASE II complex with (3R,4R,5R)-3,4-Dihydroxy-5-({[(1R)-2-hydroxy-1 phenylethyl]amino}methyl) pyrrolidin-2-one

PDB DOI: https://doi.org/10.2210/pdb3DDF/pdb

Classification: HYDROLASE
Organism(s): Drosophila melanogaster
Expression System: Drosophila melanogaster
Mutation(s): Yes

Deposited: 2008-06-05 Released: 2008-07-01
Deposition Author(s): Kuntz, D.A., Rose, D.R., Hoffman, D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.20 Å
R-Value Free: 0.151
R-Value Work: 0.115
R-Value Observed: 0.115

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.6 of the entry. See complete history.

Literature

Functionalized pyrrolidine inhibitors of human type II alpha-mannosidases as anti-cancer agents: optimizing the fit to the active site

Fiaux, H., Kuntz, D.A., Hoffman, D., Janzer, R.C., Gerber-Lemaire, S., Rose, D.R., Juillerat-Jeanneret, L.

(2008) Bioorg Med Chem 16: 7337-7346

PubMed: 18599296 Search on PubMed
DOI: https://doi.org/10.1016/j.bmc.2008.06.021
Primary Citation of Related Structures:
3DDF, 3DDG

PubMed Abstract:
Refining the chemical structure of functionalized pyrrolidine-based inhibitors of Golgi alpha-mannosidase II (GMII) to optimize binding affinity provided a lead molecule that demonstrated nanomolar competitive inhibition of alpha-mannosidases II and an optimal fit in the active site of Drosophila GMII by X-ray crystallography. Esters of this lead compound also inhibited the growth of human glioblastoma and brain-derived endothelial cells more than the growth of non-tumoral human fibroblasts, suggesting their potential for anti-cancer therapy.

Organizational Affiliation

Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.

Macromolecule Content

Total Structure Weight: 120.49 kDa
Atom Count: 10,110
Modelled Residue Count: 1,015
Deposited Residue Count: 1,045
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
alpha-mannosidase 2	A	1,045	Drosophila melanogaster	Mutation(s): 1 Gene Names: alpha-Man-II, GmII EC: 3.2.1.114
UniProt
Find proteins for Q24451 (Drosophila melanogaster) Explore Q24451 Go to UniProtKB: Q24451
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q24451
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain A	Go to GlyGen: Q24451-1
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
GB6 Query on GB6 Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	(3R,4R,5R)-3,4-dihydroxy-5-({[(1R)-2-hydroxy-1-phenylethyl]amino}methyl)pyrrolidin-2-one C₁₃ H₁₈ N₂ O₄ KRKSNZJFCXFNFF-WRWGMCAJSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
MPD Query on MPD 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]	(4S)-2-METHYL-2,4-PENTANEDIOL C₆ H₁₄ O₂ SVTBMSDMJJWYQN-YFKPBYRVSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]
MRD Query on MRD 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]	(4R)-2-METHYLPENTANE-2,4-DIOL C₆ H₁₄ O₂ SVTBMSDMJJWYQN-RXMQYKEDSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
GB6	PDBBind: 3DDF	Ki: 2.20e+4 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.20 Å
R-Value Free: 0.151
R-Value Work: 0.115
R-Value Observed: 0.115
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 68.923	α = 90
b = 109.993	β = 90
c = 138.909	γ = 90

Software Package:

Software Name	Purpose
SHELXL-97	refinement
SCALEPACK	data scaling
CNS	refinement
SHELX	refinement
PDB_EXTRACT	data extraction
ADSC	data collection
HKL-2000	data reduction
HKL-2000	data scaling
CNS	phasing
DENZO	data reduction

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2008-07-01

Deposition Author(s):

Kuntz, D.A.

Rose, D.R.

Hoffman, D.

Revision History (Full details and data files)

Version 1.0: 2008-07-01
Type: Initial release
Version 1.1: 2011-07-13
Changes: Non-polymer description, Version format compliance
Version 1.2: 2017-10-25
Changes: Refinement description
Version 1.3: 2019-07-24
Changes: Data collection, Derived calculations, Refinement description
Version 1.4: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Data collection, Database references, Derived calculations, Structure summary
Version 1.5: 2023-08-30
Changes: Data collection, Database references, Refinement description, Structure summary
Version 1.6: 2024-11-20
Changes: Structure summary