5INH

Crystal structure of Autotaxin/ENPP2 with a covalent fragment

PDB DOI: https://doi.org/10.2210/pdb5INH/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Mus musculus
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2016-03-07 Released: 2017-03-15
Deposition Author(s): Klein, M.G., Tjhen, R.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.84 Å
R-Value Free: 0.207
R-Value Work: 0.172
R-Value Observed: 0.174

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.0 of the entry. See complete history.

Literature

Repurposing Suzuki Coupling Reagents as a Directed Fragment Library Targeting Serine Hydrolases and Related Enzymes.

Lanier, M., Cole, D.C., Istratiy, Y., Klein, M.G., Schwartz, P.A., Tjhen, R., Jennings, A., Hixon, M.S.

(2017) J Med Chem 60: 5209-5215

PubMed: 28564542 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.6b01224
Primary Citation of Related Structures:
5INH

PubMed Abstract:
Serine hydrolases are susceptible to potent reversible inhibition by boronic acids. Large collections of chemically diverse boronic acid fragments are commercially available because of their utility in coupling chemistry. We repurposed the approximately 650 boronic acid reagents in our collection as a directed fragment library targeting serine hydrolases and related enzymes. Highly efficient hits (LE > 0.6) often result. The utility of the approach is illustrated with the results against autotaxin, a phospholipase implicated in cardiovascular disease.

Organizational Affiliation

Medicinal Chemistry - Gastrointestinal Drug Discovery Unit, ‡Structural Biology & Biophysics, §Modeling & Simulation-Global DMPK, Gastrointestinal Drug Discovery Unit, Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States.

Macromolecule Content

Total Structure Weight: 102.91 kDa
Atom Count: 6,709
Modelled Residue Count: 780
Deposited Residue Count: 879
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2	A	879	Mus musculus	Mutation(s): 0 Gene Names: Enpp2, Npps2, Pdnp2 EC: 3.1.4.39
UniProt
Find proteins for Q9R1E6 (Mus musculus) Explore Q9R1E6 Go to UniProtKB: Q9R1E6
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9R1E6
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	B	6		N-Glycosylation	Interactions Focus chain B Interactions & Density Focus chain B
Glycosylation Resources
GlyTouCan: G01760ZU GlyCosmos: G01760ZU GlyGen: G01760ZU

Entity ID: 3
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C	2		N-Glycosylation	Interactions Focus chain C Interactions & Density Focus chain C
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
6C1 Query on 6C1 Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A]	I [auth A]	{2-[(3-chlorophenyl)methoxy]phenyl}boronic acid C₁₃ H₁₂ B Cl O₃ CYKRFBRLRUNSDG-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A]	G [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A]	D [auth A], E [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Interactions & Density Focus chain D [auth A] Focus chain E [auth A]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain H [auth A] MOL2 format, chain H [auth A]	H [auth A]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		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 F [auth A] MOL2 format, chain F [auth A]	F [auth A]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
6C1	BindingDB: 5INH	IC50: 1000 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.84 Å
R-Value Free: 0.207
R-Value Work: 0.172
R-Value Observed: 0.174
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 62.358	α = 90
b = 80.745	β = 102.86
c = 76.48	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
HKL-2000	data reduction
HKL-2000	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2017-03-15

Deposition Author(s):

Klein, M.G.

Tjhen, R.

Revision History (Full details and data files)

Version 1.0: 2017-03-15
Type: Initial release
Version 1.1: 2017-06-21
Changes: Database references
Version 1.2: 2017-07-05
Changes: Database references
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary