5OHI

Crystal structure of autotaxin in complex with BI-2545

PDB DOI: https://doi.org/10.2210/pdb5OHI/pdb

Classification: HYDROLASE
Organism(s): Mus musculus
Expression System: Homo sapiens
Mutation(s): No

Deposited: 2017-07-17 Released: 2018-01-03
Deposition Author(s): Hoerer, S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.66 Å
R-Value Free: 0.200
R-Value Work: 0.170
R-Value Observed: 0.171

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 3.1 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: 98.68 kDa
Atom Count: 7,115
Modelled Residue Count: 778
Deposited Residue Count: 829
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	829	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

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

Entity ID: 3
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[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	D	7		N-Glycosylation	Interactions Focus chain D Interactions & Density Focus chain D
Glycosylation Resources
GlyTouCan: G16404YH GlyCosmos: G16404YH GlyGen: G16404YH

Small Molecules

Ligands 7 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
9V8 (Subject of Investigation/LOI) Query on 9V8 Download Ideal Coordinates CCD File SDF format, chain M [auth A] MOL2 format, chain M [auth A]	M [auth A]	[3,5-bis(trifluoromethyl)phenyl]methyl (1~{S},5~{R})-6-[(1~{H}-benzotriazol-5-ylcarbonylamino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate C₂₃ H₁₉ F₆ N₅ O₃ ZDOBSAPHUUUOHX-OSYLJGHBSA-N		Interactions Focus chain M [auth A] Interactions & Density Focus chain M [auth A]
P3G Query on P3G Download Ideal Coordinates CCD File SDF format, chain J [auth A] MOL2 format, chain J [auth A]	J [auth A]	3,6,9,12,15-PENTAOXAHEPTADECANE C₁₂ H₂₆ O₅ HYDWALOBQJFOMS-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Interactions & Density Focus chain J [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]	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 L [auth A] MOL2 format, chain G [auth A] MOL2 format, chain L [auth A]	G [auth A], L [auth A]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain L [auth A] Interactions & Density Focus chain G [auth A] Focus chain L [auth A]
K Query on K Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 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]	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] MOL2 format, chain H [auth A]	H [auth A]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Interactions & Density Focus chain H [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.66 Å
R-Value Free: 0.200
R-Value Work: 0.170
R-Value Observed: 0.171
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 61.057	α = 90
b = 93.779	β = 94.91
c = 75.695	γ = 90

Software Package:

Software Name	Purpose
autoPROC	data collection
XDS	data reduction
autoPROC	data scaling
Aimless	data scaling
BUSTER	refinement
PHASER	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.

Revision History (Full details and data files)

Version 1.0: 2018-01-03
Type: Initial release
Version 2.0: 2018-10-03
Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Structure summary
Version 3.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Refinement description, Structure summary
Version 3.1: 2024-01-17
Changes: Data collection, Database references, Refinement description, Structure summary