5OLB

crystal structure of autotaxin in complex with PF-8380

PDB DOI: https://doi.org/10.2210/pdb5OLB/pdb

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

Deposited: 2017-07-27 Released: 2018-01-03
Deposition Author(s): Hoerer, S., Lammens, A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.82 Å
R-Value Free: 0.191
R-Value Work: 0.172
R-Value Observed: 0.172

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 2.2 of the entry. See complete history.

Literature

Discovery of BI-2545: A Novel Autotaxin Inhibitor That Significantly Reduces LPA Levels in Vivo.

Kuttruff, C.A., Ferrara, M., Bretschneider, T., Hoerer, S., Handschuh, S., Nosse, B., Romig, H., Nicklin, P., Roth, G.J.

(2017) ACS Med Chem Lett 8: 1252-1257

PubMed: 29259743 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.7b00312
Primary Citation of Related Structures:
5OHI, 5OLB

PubMed Abstract:
In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies.

Organizational Affiliation

Medicinal Chemistry, Drug Discovery Sciences, and Immunology & Respiratory, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.

Macromolecule Content

Total Structure Weight: 100.94 kDa
Atom Count: 7,550
Modelled Residue Count: 785
Deposited Residue Count: 844
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Ectonucleotide pyrophosphatase/phosphodiesterase family member 2	A	844	Mus musculus	Mutation(s): 0 Gene Names: Enpp2, Npps2, Pdnp2 EC: 3.1.4.39 (PDB Primary Data), 3.1.4.4 (UniProt)
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
Glycosylation
Glycosylation Sites: 3	Glycosylation Focus chain A	Go to GlyGen: Q9R1E6-1
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)][alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose	B	6		N-Glycosylation	Interactions Focus chain B Interactions & Density Focus chain B
Glycosylation Resources
GlyTouCan: G17601US GlyCosmos: G17601US GlyGen: G17601US

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

Entity ID: 4
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	D	6		N-Glycosylation	Interactions Focus chain D Interactions & Density Focus chain D
Glycosylation Resources
GlyTouCan: G47410OF GlyCosmos: G47410OF GlyGen: G47410OF

Small Molecules

Ligands 8 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
6ZO (Subject of Investigation/LOI) Query on 6ZO Download Ideal Coordinates CCD File SDF format, chain O [auth A] MOL2 format, chain O [auth A] mmCIF format, chain O [auth A]	O [auth A]	(3,5-dichlorophenyl)methyl 4-[3-oxo-3-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)propyl]piperazine-1-carboxylate C₂₂ H₂₁ Cl₂ N₃ O₅ JMSUDQYHPSNBSN-UHFFFAOYSA-N		Interactions Focus chain O [auth A] Interactions & Density Focus chain O [auth A]
PGE Query on PGE Download Ideal Coordinates CCD File SDF format, chain M [auth A] MOL2 format, chain M [auth A] mmCIF format, chain M [auth A]	M [auth A]	TRIETHYLENE GLYCOL C₆ H₁₄ O₄ ZIBGPFATKBEMQZ-UHFFFAOYSA-N		Interactions Focus chain M [auth A] Interactions & Density Focus chain M [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain N [auth A] MOL2 format, chain N [auth A] mmCIF format, chain N [auth A]	N [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain N [auth A] Interactions & Density Focus chain N [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	E [auth A], F [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain J [auth A] MOL2 format, chain G [auth A] MOL2 format, chain J [auth A] mmCIF format, chain G [auth A] mmCIF format, chain J [auth A]	G [auth A], J [auth A]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain J [auth A] Interactions & Density Focus chain G [auth A] Focus chain J [auth A]
K Query on K Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A] mmCIF format, chain I [auth A]	I [auth A]	POTASSIUM ION K NPYPAHLBTDXSSS-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain K [auth A] MOL2 format, chain K [auth A] mmCIF format, chain K [auth A]	K [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain K [auth A] Interactions & Density Focus chain K [auth A]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain L [auth A] MOL2 format, chain H [auth A] MOL2 format, chain L [auth A] mmCIF format, chain H [auth A] mmCIF format, chain L [auth A]	H [auth A], L [auth A]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Focus chain L [auth A] Interactions & Density Focus chain H [auth A] Focus chain L [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
6ZO	BindingDB: 5OLB	IC50: min: 1.1, max: 2800 (nM) from 16 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.82 Å
R-Value Free: 0.191
R-Value Work: 0.172
R-Value Observed: 0.172
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 124.734	α = 90
b = 100.045	β = 90
c = 78.778	γ = 90

Software Package:

Software Name	Purpose
autoPROC	data collection
XDS	data reduction
Aimless	data scaling
BUSTER	refinement
PHENIX	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2018-01-03

Deposition Author(s):

Hoerer, S.

Lammens, A.

Revision History (Full details and data files)

Version 1.0: 2018-01-03
Type: Initial release
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Refinement description, Structure summary
Version 2.1: 2024-01-17
Changes: Advisory, Data collection, Database references, Refinement description, Structure summary
Version 2.2: 2024-10-23
Changes: Structure summary