6ZDM

Crystal structure of human heparanase in complex with a N',6O'-bis-sulfated 4-methylumbelliferyl heparan sulfate disaccharide

PDB DOI: https://doi.org/10.2210/pdb6ZDM/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Trichoplusia ni
Mutation(s): No

Deposited: 2020-06-14 Released: 2020-10-21
Deposition Author(s): Wu, L., Davies, G.J.
Funding Organization(s): European Research Council (ERC), Australian Research Council (ARC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.71 Å
R-Value Free: 0.241
R-Value Work: 0.179

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Structural insights into heparanase activity using a fluorogenic heparan sulfate disaccharide.

Wu, L., Wimmer, N., Davies, G.J., Ferro, V.

(2020) Chem Commun (Camb) 56: 13780-13783

PubMed: 33073275 Search on PubMed
DOI: https://doi.org/10.1039/d0cc05932c
Primary Citation of Related Structures:
6ZDM

PubMed Abstract:
A synthetic heparan sulfate disaccharide has been assessed as a fluorogenic heparanase substrate, enabling enzyme turnover and inhibition kinetics measurements despite slow turnover. Crystal structures with human heparanase also provide the first ever observation of a substrate in an activated 1S3 conformation, highlighting previously unknown interactions involved in enzymatic processing. Our data provide insights into the heparanase catalytic mechanism, and will inform the design of improved heparanase substrates and inhibitors.

Organizational Affiliation

Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK. [email protected].

Macromolecule Content

Total Structure Weight: 53.71 kDa
Atom Count: 3,930
Modelled Residue Count: 457
Deposited Residue Count: 466
Unique protein chains: 2

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Heparanase	A [auth AAA]	389	Homo sapiens	Mutation(s): 0 Gene Names: HPSE, HEP, HPA, HPA1, HPR1, HPSE1, HSE1 EC: 3.2.1.166
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y251 (Homo sapiens) Explore Q9Y251 Go to UniProtKB: Q9Y251
PHAROS: Q9Y251 GTEx: ENSG00000173083
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9Y251
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain A [auth AAA]	Go to GlyGen: Q9Y251-1
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Heparanase	B [auth BBB]	77	Homo sapiens	Mutation(s): 0 Gene Names: HPSE, HEP, HPA, HPA1, HPR1, HPSE1, HSE1 EC: 3.2.1.166
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y251 (Homo sapiens) Explore Q9Y251 Go to UniProtKB: Q9Y251
PHAROS: Q9Y251 GTEx: ENSG00000173083
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9Y251
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
QG2 (Subject of Investigation/LOI) Query on QG2 Download Ideal Coordinates CCD File SDF format, chain E [auth AAA] MOL2 format, chain E [auth AAA] mmCIF format, chain E [auth AAA]	E [auth AAA]	(2~{S},3~{S},4~{R},5~{R},6~{S})-3-[(2~{R},3~{R},4~{R},5~{S},6~{R})-4,5-bis(oxidanyl)-3-(sulfoamino)-6-(sulfooxymethyl)oxan-2-yl]oxy-6-(4-methyl-2-oxidanylidene-chromen-7-yl)oxy-4,5-bis(oxidanyl)oxane-2-carboxylic acid C₂₂ H₂₇ N O₁₉ S₂ VWVHHIREMFENNG-XOAMEYKJSA-N		Interactions Focus chain E [auth AAA] Interactions & Density Focus chain E [auth AAA]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain C [auth AAA] MOL2 format, chain C [auth AAA] mmCIF format, chain C [auth AAA]	C [auth AAA]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain C [auth AAA] Interactions & Density Focus chain C [auth AAA]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain F [auth AAA] SDF format, chain G [auth AAA] SDF format, chain H [auth AAA] SDF format, chain I [auth AAA] SDF format, chain J [auth AAA] MOL2 format, chain F [auth AAA] MOL2 format, chain G [auth AAA] MOL2 format, chain H [auth AAA] MOL2 format, chain I [auth AAA] MOL2 format, chain J [auth AAA] mmCIF format, chain F [auth AAA] mmCIF format, chain G [auth AAA] mmCIF format, chain H [auth AAA] mmCIF format, chain I [auth AAA] mmCIF format, chain J [auth AAA]	F [auth AAA], G [auth AAA], H [auth AAA], I [auth AAA], J [auth AAA]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain F [auth AAA] Focus chain G [auth AAA] Focus chain H [auth AAA] Focus chain I [auth AAA] Focus chain J [auth AAA] Interactions & Density Focus chain F [auth AAA] Focus chain G [auth AAA] Focus chain H [auth AAA] Focus chain I [auth AAA] Focus chain J [auth AAA]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain D [auth AAA] MOL2 format, chain D [auth AAA] mmCIF format, chain D [auth AAA]	D [auth AAA]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain D [auth AAA] Interactions & Density Focus chain D [auth AAA]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.71 Å
R-Value Free: 0.241
R-Value Work: 0.179
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 44.974	α = 90
b = 70.856	β = 97.128
c = 78.455	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
xia2	data reduction
STARANISO	data scaling
REFMAC	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2020-10-21

Deposition Author(s):

Wu, L.

Davies, G.J.

Funding Organization	Location	Grant Number
European Research Council (ERC)	United Kingdom	ERC-2012-AdG-322942
Australian Research Council (ARC)	Australia	DP170104431

Revision History (Full details and data files)

Version 1.0: 2020-10-21
Type: Initial release
Version 1.1: 2020-11-04
Changes: Database references
Version 1.2: 2020-11-18
Changes: Database references
Version 1.3: 2024-01-24
Changes: Data collection, Database references, Derived calculations, Refinement description
Version 1.4: 2024-11-06
Changes: Structure summary