9FXW | pdb_00009fxw

Crystal Structure of Autotaxin (ENPP2) with Type VI Inhibitor, a Novel Class of Inhibitors with Three-Point Lock Binding Mode

PDB DOI: https://doi.org/10.2210/pdb9FXW/pdb

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

Deposited: 2024-07-02 Released: 2025-04-23
Deposition Author(s): Borza, R., Joosten, R.P., Perrakis, A.
Funding Organization(s): Oncode Institute

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.95 Å
R-Value Free:
0.201 (Depositor), 0.202 (DCC)
R-Value Work:
0.174 (Depositor), 0.175 (DCC)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode.

Desroy, N., Borza, R., Heiermann, J., Triballeau, N., Joncour, A., Bienvenu, N., Hengeveld, W.J., Springer, J., Galien, R., Joosten, R.P., Perrakis, A., Heckmann, B.

(2025) Bioorg Med Chem 124: 118181-118181

PubMed: 40233422 Search on PubMed
DOI: https://doi.org/10.1016/j.bmc.2025.118181
Primary Citation of Related Structures:
9FTN, 9FXU, 9FXW, 9FXY

PubMed Abstract:
Autotaxin (ATX) is a circulating enzyme that plays a major role in the production of the signaling mediator lysophosphatidic acid (LPA). A role for ATX/LPA signaling has been described in multiple disease areas, including fibrosis and cancer. ATX inhibitors are classified in five types (I-V) depending on how they target parts of the tripartite site (active site, pocket and tunnel). We set to explore a "penultimate" type of inhibitors, targeting all these three parts at once. Designing new analogs extending on an ethyl group of the type IV GLPG1690 compound, yielded potent new molecules. Co-crystal structures confirmed compounds that utilize a three-point lock binding mode. The most potent "type VI" inhibitors, 4 and 41, displayed increased inhibitory activity (∼40-fold) compared to the type IV close analog 3. Type VI inhibitors 4 and 41 showed cellular and phenotypic activity similar to type IV inhibitor GLPG1690. Identification of this new binding mode completes this combinatorial puzzle in inhibitor design and calls for further investigation to characterize potential therapeutic benefit.

Organizational Affiliation

Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France. Electronic address: nicolas.desroy@glpg.com.

Macromolecule Content

Total Structure Weight: 99.14 kDa
Atom Count: 6,953
Modeled Residue Count: 779
Deposited Residue Count: 807
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Isoform 2 of Autotaxin	A	807	Rattus norvegicus	Mutation(s): 2 Gene Names: Enpp2, Atx, Npps2 EC: 3.1.4.39 (PDB Primary Data), 3.1.4.4 (PDB Primary Data)
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-(1-6)-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	B	5		N-Glycosylation	Interactions Focus chain B Interactions & Density Focus chain B
Glycosylation Resources
GlyTouCan: G94626GC GlyCosmos: G94626GC GlyGen: G94626GC

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1IG0 Query on A1IG0 Download Ideal Coordinates CCD File SDF format, chain H [auth A] MOL2 format, chain H [auth A] mmCIF format, chain H [auth A]	H [auth A]	N-(3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide C₃₃ H₃₃ F N₈ O₅ S₂ WEWIOVRRMFIOFU-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Interactions & Density Focus chain H [auth A]
IOD Query on IOD Download Ideal Coordinates CCD File SDF format, chain BB [auth A] SDF format, chain CB [auth A] SDF format, chain DB [auth A] SDF format, chain EB [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain GA [auth A] SDF format, chain J [auth A] SDF format, chain KA [auth A] SDF format, chain LA [auth A] SDF format, chain NA [auth A] SDF format, chain TA [auth A] SDF format, chain UA [auth A] SDF format, chain VA [auth A] SDF format, chain WA [auth A] MOL2 format, chain BB [auth A] MOL2 format, chain CB [auth A] MOL2 format, chain DB [auth A] MOL2 format, chain EB [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain GA [auth A] MOL2 format, chain J [auth A] MOL2 format, chain KA [auth A] MOL2 format, chain LA [auth A] MOL2 format, chain NA [auth A] MOL2 format, chain TA [auth A] MOL2 format, chain UA [auth A] MOL2 format, chain VA [auth A] MOL2 format, chain WA [auth A] mmCIF format, chain BB [auth A] mmCIF format, chain CB [auth A] mmCIF format, chain DB [auth A] mmCIF format, chain EB [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain GA [auth A] mmCIF format, chain J [auth A] mmCIF format, chain KA [auth A] mmCIF format, chain LA [auth A] mmCIF format, chain NA [auth A] mmCIF format, chain TA [auth A] mmCIF format, chain UA [auth A] mmCIF format, chain VA [auth A] mmCIF format, chain WA [auth A]	BB [auth A] CB [auth A] DB [auth A] EB [auth A] F [auth A] BB [auth A], CB [auth A], DB [auth A], EB [auth A], F [auth A], G [auth A], GA [auth A], J [auth A], KA [auth A], LA [auth A], NA [auth A], TA [auth A], UA [auth A], VA [auth A], WA [auth A]	IODIDE ION I XMBWDFGMSWQBCA-UHFFFAOYSA-M		Interactions Focus chain BB [auth A] Focus chain CB [auth A] Focus chain DB [auth A] Focus chain EB [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain GA [auth A] Focus chain J [auth A] Focus chain KA [auth A] Focus chain LA [auth A] Focus chain NA [auth A] Focus chain TA [auth A] Focus chain UA [auth A] Focus chain VA [auth A] Focus chain WA [auth A] Interactions & Density Focus chain BB [auth A] Focus chain CB [auth A] Focus chain DB [auth A] Focus chain EB [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain GA [auth A] Focus chain J [auth A] Focus chain KA [auth A] Focus chain LA [auth A] Focus chain NA [auth A] Focus chain TA [auth A] Focus chain UA [auth A] Focus chain VA [auth A] Focus chain WA [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain AA [auth A] SDF format, chain CA [auth A] SDF format, chain GB [auth A] SDF format, chain OA [auth A] SDF format, chain FA [auth A] SDF format, chain MA [auth A] SDF format, chain XA [auth A] SDF format, chain Y [auth A] SDF format, chain Z [auth A] MOL2 format, chain AA [auth A] MOL2 format, chain CA [auth A] MOL2 format, chain GB [auth A] MOL2 format, chain OA [auth A] MOL2 format, chain FA [auth A] MOL2 format, chain MA [auth A] MOL2 format, chain XA [auth A] MOL2 format, chain Y [auth A] MOL2 format, chain Z [auth A] mmCIF format, chain AA [auth A] mmCIF format, chain CA [auth A] mmCIF format, chain GB [auth A] mmCIF format, chain OA [auth A] mmCIF format, chain FA [auth A] mmCIF format, chain MA [auth A] mmCIF format, chain XA [auth A] mmCIF format, chain Y [auth A] mmCIF format, chain Z [auth A]	AA [auth A] CA [auth A] FA [auth A] GB [auth A] MA [auth A] AA [auth A], CA [auth A], FA [auth A], GB [auth A], MA [auth A], OA [auth A], XA [auth A], Y [auth A], Z [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain AA [auth A] Focus chain CA [auth A] Focus chain FA [auth A] Focus chain GB [auth A] Focus chain MA [auth A] Focus chain OA [auth A] Focus chain XA [auth A] Focus chain Y [auth A] Focus chain Z [auth A] Interactions & Density Focus chain AA [auth A] Focus chain CA [auth A] Focus chain FA [auth A] Focus chain GB [auth A] Focus chain MA [auth A] Focus chain OA [auth A] Focus chain XA [auth A] Focus chain Y [auth A] Focus chain Z [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A]	C [auth A], D [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A]
SCN Query on SCN Download Ideal Coordinates CCD File SDF format, chain AB [auth A] SDF format, chain BA [auth A] SDF format, chain DA [auth A] SDF format, chain EA [auth A] SDF format, chain FB [auth A] SDF format, chain HA [auth A] SDF format, chain HB [auth A] SDF format, chain I [auth A] SDF format, chain IA [auth A] SDF format, chain JA [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 O [auth A] SDF format, chain P [auth A] SDF format, chain PA [auth A] SDF format, chain Q [auth A] SDF format, chain QA [auth A] SDF format, chain R [auth A] SDF format, chain RA [auth A] SDF format, chain S [auth A] SDF format, chain SA [auth A] SDF format, chain T [auth A] SDF format, chain U [auth A] SDF format, chain V [auth A] SDF format, chain W [auth A] SDF format, chain X [auth A] SDF format, chain YA [auth A] SDF format, chain ZA [auth A] MOL2 format, chain AB [auth A] MOL2 format, chain BA [auth A] MOL2 format, chain DA [auth A] MOL2 format, chain EA [auth A] MOL2 format, chain FB [auth A] MOL2 format, chain HA [auth A] MOL2 format, chain HB [auth A] MOL2 format, chain I [auth A] MOL2 format, chain IA [auth A] MOL2 format, chain JA [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 O [auth A] MOL2 format, chain P [auth A] MOL2 format, chain PA [auth A] MOL2 format, chain Q [auth A] MOL2 format, chain QA [auth A] MOL2 format, chain R [auth A] MOL2 format, chain RA [auth A] MOL2 format, chain S [auth A] MOL2 format, chain SA [auth A] MOL2 format, chain T [auth A] MOL2 format, chain U [auth A] MOL2 format, chain V [auth A] MOL2 format, chain W [auth A] MOL2 format, chain X [auth A] MOL2 format, chain YA [auth A] MOL2 format, chain ZA [auth A] mmCIF format, chain AB [auth A] mmCIF format, chain BA [auth A] mmCIF format, chain DA [auth A] mmCIF format, chain EA [auth A] mmCIF format, chain FB [auth A] mmCIF format, chain HA [auth A] mmCIF format, chain HB [auth A] mmCIF format, chain I [auth A] mmCIF format, chain IA [auth A] mmCIF format, chain JA [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 O [auth A] mmCIF format, chain P [auth A] mmCIF format, chain PA [auth A] mmCIF format, chain Q [auth A] mmCIF format, chain QA [auth A] mmCIF format, chain R [auth A] mmCIF format, chain RA [auth A] mmCIF format, chain S [auth A] mmCIF format, chain SA [auth A] mmCIF format, chain T [auth A] mmCIF format, chain U [auth A] mmCIF format, chain V [auth A] mmCIF format, chain W [auth A] mmCIF format, chain X [auth A] mmCIF format, chain YA [auth A] mmCIF format, chain ZA [auth A]	AB [auth A] BA [auth A] DA [auth A] EA [auth A] FB [auth A] AB [auth A], BA [auth A], DA [auth A], EA [auth A], FB [auth A], HA [auth A], HB [auth A], I [auth A], IA [auth A], JA [auth A], K [auth A], L [auth A], M [auth A], N [auth A], O [auth A], P [auth A], PA [auth A], Q [auth A], QA [auth A], R [auth A], RA [auth A], S [auth A], SA [auth A], T [auth A], U [auth A], V [auth A], W [auth A], X [auth A], YA [auth A], ZA [auth A]	THIOCYANATE ION C N S ZMZDMBWJUHKJPS-UHFFFAOYSA-M		Interactions Focus chain AB [auth A] Focus chain BA [auth A] Focus chain DA [auth A] Focus chain EA [auth A] Focus chain FB [auth A] Focus chain HA [auth A] Focus chain HB [auth A] Focus chain I [auth A] Focus chain IA [auth A] Focus chain JA [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain P [auth A] Focus chain PA [auth A] Focus chain Q [auth A] Focus chain QA [auth A] Focus chain R [auth A] Focus chain RA [auth A] Focus chain S [auth A] Focus chain SA [auth A] Focus chain T [auth A] Focus chain U [auth A] Focus chain V [auth A] Focus chain W [auth A] Focus chain X [auth A] Focus chain YA [auth A] Focus chain ZA [auth A] Interactions & Density Focus chain AB [auth A] Focus chain BA [auth A] Focus chain DA [auth A] Focus chain EA [auth A] Focus chain FB [auth A] Focus chain HA [auth A] Focus chain HB [auth A] Focus chain I [auth A] Focus chain IA [auth A] Focus chain JA [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain P [auth A] Focus chain PA [auth A] Focus chain Q [auth A] Focus chain QA [auth A] Focus chain R [auth A] Focus chain RA [auth A] Focus chain S [auth A] Focus chain SA [auth A] Focus chain T [auth A] Focus chain U [auth A] Focus chain V [auth A] Focus chain W [auth A] Focus chain X [auth A] Focus chain YA [auth A] Focus chain ZA [auth A]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]