5M0M

Structure-based evolution of a hybrid steroid series of Autotaxin inhibitors

PDB DOI: https://doi.org/10.2210/pdb5M0M/pdb

Classification: HYDROLASE
Organism(s): Rattus norvegicus
Expression System: Homo sapiens
Mutation(s): Yes

Deposited: 2016-10-05 Released: 2017-08-16
Deposition Author(s): Keune, W.-J., Heidebrecht, T., Perrakis, A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.249
R-Value Work: 0.201
R-Value Observed: 0.203

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

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators.

Keune, W.J., Potjewyd, F., Heidebrecht, T., Salgado-Polo, F., Macdonald, S.J., Chelvarajan, L., Abdel Latif, A., Soman, S., Morris, A.J., Watson, A.J., Jamieson, C., Perrakis, A.

(2017) J Med Chem 60: 2006-2017

PubMed: 28165241 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.6b01743
Primary Citation of Related Structures:
5M0D, 5M0E, 5M0M, 5M0S

PubMed Abstract:
Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

Organizational Affiliation

Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.

Macromolecule Content

Total Structure Weight: 100.66 kDa
Atom Count: 6,598
Modelled Residue Count: 774
Deposited Residue Count: 827
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	827	Rattus norvegicus	Mutation(s): 4 Gene Names: Enpp2, Atx, Npps2 EC: 3.1.4.39 (PDB Primary Data), 3.1.4.4 (UniProt)
UniProt
Find proteins for Q64610 (Rattus norvegicus) Explore Q64610 Go to UniProtKB: Q64610
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q64610
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain A	Go to GlyGen: Q64610-1
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)]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	B	9		N-Glycosylation	Interactions Focus chain B Interactions & Density Focus chain B
Glycosylation Resources
GlyTouCan: G37135JQ GlyCosmos: G37135JQ GlyGen: G37135JQ

Small Molecules

Ligands 8 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
7CF Query on 7CF Download Ideal Coordinates CCD File SDF format, chain R [auth A] MOL2 format, chain R [auth A] mmCIF format, chain R [auth A]	R [auth A]	[3,5-bis(chloranyl)phenyl]methyl (3~{R})-3-[[(4~{R})-4-[(3~{R},5~{S},7~{S},8~{R},9~{S},10~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-3,7-bis(oxidanyl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]pyrrolidine-1-carboxylate C₃₆ H₅₂ Cl₂ N₂ O₅ ZEXNABOXYLWWLJ-WGEHOESMSA-N		Interactions Focus chain R [auth A] Interactions & Density Focus chain R [auth A]
NKP Query on NKP Download Ideal Coordinates CCD File SDF format, chain LA [auth A] MOL2 format, chain LA [auth A] mmCIF format, chain LA [auth A]	LA [auth A]	(2R)-2-hydroxy-3-(phosphonooxy)propyl (9E)-octadec-9-enoate C₂₁ H₄₁ O₇ P WRGQSWVCFNIUNZ-SQUSKLHYSA-N		Interactions Focus chain LA [auth A] Interactions & Density Focus chain LA [auth A]
IOD Query on IOD Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain H [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain H [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain H [auth A]	C [auth A] D [auth A] E [auth A] F [auth A] G [auth A] C [auth A], D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], L [auth A], M [auth A], N [auth A]	IODIDE ION I XMBWDFGMSWQBCA-UHFFFAOYSA-M		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain AA [auth A] SDF format, chain BA [auth A] SDF format, chain CA [auth A] SDF format, chain DA [auth A] SDF format, chain EA [auth A] SDF format, chain FA [auth A] SDF format, chain GA [auth A] MOL2 format, chain AA [auth A] MOL2 format, chain BA [auth A] MOL2 format, chain CA [auth A] MOL2 format, chain DA [auth A] MOL2 format, chain EA [auth A] MOL2 format, chain FA [auth A] MOL2 format, chain GA [auth A] mmCIF format, chain AA [auth A] mmCIF format, chain BA [auth A] mmCIF format, chain CA [auth A] mmCIF format, chain DA [auth A] mmCIF format, chain EA [auth A] mmCIF format, chain FA [auth A] mmCIF format, chain GA [auth A]	AA [auth A] BA [auth A] CA [auth A] DA [auth A] EA [auth A] AA [auth A], BA [auth A], CA [auth A], DA [auth A], EA [auth A], FA [auth A], GA [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain AA [auth A] Focus chain BA [auth A] Focus chain CA [auth A] Focus chain DA [auth A] Focus chain EA [auth A] Focus chain FA [auth A] Focus chain GA [auth A] Interactions & Density Focus chain AA [auth A] Focus chain BA [auth A] Focus chain CA [auth A] Focus chain DA [auth A] Focus chain EA [auth A] Focus chain FA [auth A] Focus chain GA [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain P [auth A] SDF format, chain O [auth A] MOL2 format, chain P [auth A] MOL2 format, chain O [auth A] mmCIF format, chain P [auth A] mmCIF format, chain O [auth A]	O [auth A], P [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain O [auth A] Focus chain P [auth A] Interactions & Density Focus chain O [auth A] Focus chain P [auth A]
SCN Query on SCN Download Ideal Coordinates CCD File SDF format, chain HA [auth A] SDF format, chain IA [auth A] SDF format, chain JA [auth A] SDF format, chain KA [auth A] SDF format, chain V [auth A] SDF format, chain W [auth A] SDF format, chain X [auth A] SDF format, chain Y [auth A] SDF format, chain Z [auth A] SDF format, chain U [auth A] MOL2 format, chain HA [auth A] MOL2 format, chain IA [auth A] MOL2 format, chain JA [auth A] MOL2 format, chain KA [auth A] MOL2 format, chain V [auth A] MOL2 format, chain W [auth A] MOL2 format, chain X [auth A] MOL2 format, chain Y [auth A] MOL2 format, chain Z [auth A] MOL2 format, chain U [auth A] mmCIF format, chain HA [auth A] mmCIF format, chain IA [auth A] mmCIF format, chain JA [auth A] mmCIF format, chain KA [auth A] mmCIF format, chain V [auth A] mmCIF format, chain W [auth A] mmCIF format, chain X [auth A] mmCIF format, chain Y [auth A] mmCIF format, chain Z [auth A] mmCIF format, chain U [auth A]	HA [auth A] IA [auth A] JA [auth A] KA [auth A] U [auth A] HA [auth A], IA [auth A], JA [auth A], KA [auth A], U [auth A], V [auth A], W [auth A], X [auth A], Y [auth A], Z [auth A]	THIOCYANATE ION C N S ZMZDMBWJUHKJPS-UHFFFAOYSA-M		Interactions Focus chain HA [auth A] Focus chain IA [auth A] Focus chain JA [auth A] Focus chain KA [auth A] Focus chain U [auth A] Focus chain V [auth A] Focus chain W [auth A] Focus chain X [auth A] Focus chain Y [auth A] Focus chain Z [auth A] Interactions & Density Focus chain HA [auth A] Focus chain IA [auth A] Focus chain JA [auth A] Focus chain KA [auth A] Focus chain U [auth A] Focus chain V [auth A] Focus chain W [auth A] Focus chain X [auth A] Focus chain Y [auth A] Focus chain Z [auth A]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain Q [auth A] MOL2 format, chain Q [auth A] mmCIF format, chain Q [auth A]	Q [auth A]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain Q [auth A] Interactions & Density Focus chain Q [auth A]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain S [auth A] SDF format, chain T [auth A] MOL2 format, chain S [auth A] MOL2 format, chain T [auth A] mmCIF format, chain S [auth A] mmCIF format, chain T [auth A]	S [auth A], T [auth A]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain S [auth A] Focus chain T [auth A] Interactions & Density Focus chain S [auth A] Focus chain T [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
7CF	BindingDB: 5M0M	Ki: 6 (nM) from 1 assay(s)
7CF	BindingDB: 5M0M	IC50: min: 20, max: 20 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.10 Å
R-Value Free: 0.249
R-Value Work: 0.201
R-Value Observed: 0.203
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 62.995	α = 90
b = 89.173	β = 103.12
c = 77.289	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
Aimless	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2017-08-16

Deposition Author(s):

Keune, W.-J.

Heidebrecht, T.

Perrakis, A.

Revision History (Full details and data files)

Version 1.0: 2017-08-16
Type: Initial release
Version 1.1: 2019-10-16
Changes: Data collection
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2024-01-17
Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary
Version 2.2: 2024-11-20
Changes: Structure summary