3AM9

Complex of bovine xanthine dehydrogenase and trihydroxy FYX-051

PDB DOI: https://doi.org/10.2210/pdb3AM9/pdb

Classification: OXIDOREDUCTASE
Organism(s): Bos taurus
Mutation(s): No

Deposited: 2010-08-18 Released: 2010-11-03
Deposition Author(s): Matsumoto, K., Okamoto, K., Ashizawa, N., Matsumura, T., Kusano, T., Nishino, T.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.17 ?
R-Value Free: 0.243
R-Value Work: 0.174
R-Value Observed: 0.177

Starting Model: experimental
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Ligand Structure Quality Assessment

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Literature

FYX-051: A Novel and Potent Hybrid-Type Inhibitor of Xanthine Oxidoreductase

Matsumoto, K., Okamoto, K., Ashizawa, N., Nishino, T.

(2011) J Pharmacol Exp Ther 336: 95-103

PubMed: 20952484 Search on PubMed
DOI: https://doi.org/10.1124/jpet.110.174540
Primary Citation of Related Structures:
3AM9

PubMed Abstract:
4-[5-(Pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (FYX-051) is a potent inhibitor of bovine milk xanthine oxidoreductase (XOR). Steady-state kinetics study showed that it initially behaved as a competitive-type inhibitor with a K(i) value of 5.7 × 10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as reported previously (Proc Natl Acad Sci USA 101:7931-7936, 2004). Thus, FYX-051 is a hybrid-type inhibitor exhibiting both structure- and mechanism-based inhibition. The FYX-051-XOR complex decomposed with a half-life of 20.4 h, but the enzyme activity did not fully recover. This was found to be caused by XOR-mediated conversion of FYX-051 to 4-[5-(2-hydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (2-hydroxy-FYX-051), as well as formation of 6-hydroxy-4-[5-(2-hydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (dihydroxy-FYX-051) and 4-[5-(2,6-dihydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]-6-hydroxypyridine-2-carbonitrile (trihydroxy-FYX-051) during prolonged incubation for up to 72 h. A distinct charge-transfer band was observed concomitantly with the formation of the trihydroxy-FYX-051-XOR complex. Crystallographic analysis of the charge-transfer complex indicated that a Mo-nitrogen-carbon bond was formed between molybdenum of XOR and the nitrile group of trihydroxy-FYX-051. FYX-051 showed a potent and long-lasting hypouricemic effect in a rat model of potassium oxonate-induced hyperuricemia, and it seems to be a promising candidate for the clinical treatment of hyperuricemia.

Organizational Affiliation

Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Macromolecule Content

Total Structure Weight: 298.43 kDa
Atom Count: 22,226
Modelled Residue Count: 2,584
Deposited Residue Count: 2,664
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Xanthine dehydrogenase/oxidase	A, B	1,332	Bos taurus	Mutation(s): 0 EC: 1.17.1.4 (PDB Primary Data), 1.17.3.2 (PDB Primary Data)
UniProt
Find proteins for P80457 (Bos taurus) Explore P80457 Go to UniProtKB: P80457
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P80457
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 8 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
FAD Query on FAD Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain O [auth B] MOL2 format, chain F [auth A] MOL2 format, chain O [auth B] mmCIF format, chain F [auth A] mmCIF format, chain O [auth B]	F [auth A], O [auth B]	FLAVIN-ADENINE DINUCLEOTIDE C₂₇ H₃₃ N₉ O₁₅ P₂ VWWQXMAJTJZDQX-UYBVJOGSSA-N		Interactions Focus chain F [auth A] Focus chain O [auth B] Interactions & Density Focus chain F [auth A] Focus chain O [auth B]
MTE Query on MTE Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain Q [auth B] MOL2 format, chain H [auth A] MOL2 format, chain Q [auth B] mmCIF format, chain H [auth A] mmCIF format, chain Q [auth B]	H [auth A], Q [auth B]	PHOSPHONIC ACIDMONO-(2-AMINO-5,6-DIMERCAPTO-4-OXO-3,7,8A,9,10,10A-HEXAHYDRO-4H-8-OXA-1,3,9,10-TETRAAZA-ANTHRACEN-7-YLMETHYL)ESTER C₁₀ H₁₄ N₅ O₆ P S₂ HPEUEJRPDGMIMY-IFQPEPLCSA-N		Interactions Focus chain H [auth A] Focus chain Q [auth B] Interactions & Density Focus chain H [auth A] Focus chain Q [auth B]
FYO Query on FYO Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain S [auth B] MOL2 format, chain J [auth A] MOL2 format, chain S [auth B] mmCIF format, chain J [auth A] mmCIF format, chain S [auth B]	J [auth A], S [auth B]	4-[5-(2,6-dioxo-1,2,3,6-tetrahydropyridin-4-yl)-1H-1,2,4-triazol-3-yl]-6-oxo-1,6-dihydropyridine-2-carbonitrile C₁₃ H₈ N₆ O₃ YUNURAZDMHEFGV-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain S [auth B] Interactions & Density Focus chain J [auth A] Focus chain S [auth B]
FES Query on FES Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain C [auth A] SDF format, chain L [auth B] SDF format, chain M [auth B] MOL2 format, chain D [auth A] MOL2 format, chain C [auth A] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] mmCIF format, chain D [auth A] mmCIF format, chain C [auth A] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B]	C [auth A], D [auth A], L [auth B], M [auth B]	FE2/S2 (INORGANIC) CLUSTER Fe₂ S₂ NIXDOXVAJZFRNF-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain L [auth B] Focus chain M [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain L [auth B] Focus chain M [auth B]
MOS Query on MOS Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain R [auth B] MOL2 format, chain I [auth A] MOL2 format, chain R [auth B] mmCIF format, chain I [auth A] mmCIF format, chain R [auth B]	I [auth A], R [auth B]	DIOXOTHIOMOLYBDENUM(VI) ION H Mo O₂ S BDSRWPHSAKXXRG-UHFFFAOYSA-M		Interactions Focus chain I [auth A] Focus chain R [auth B] Interactions & Density Focus chain I [auth A] Focus chain R [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain T [auth B] SDF format, chain V [auth B] MOL2 format, chain T [auth B] MOL2 format, chain V [auth B] mmCIF format, chain T [auth B] mmCIF format, chain V [auth B]	T [auth B], V [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain T [auth B] Focus chain V [auth B] Interactions & Density Focus chain T [auth B] Focus chain V [auth B]
BCT Query on BCT Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain P [auth B] MOL2 format, chain G [auth A] MOL2 format, chain P [auth B] mmCIF format, chain G [auth A] mmCIF format, chain P [auth B]	G [auth A], P [auth B]	BICARBONATE ION C H O₃ BVKZGUZCCUSVTD-UHFFFAOYSA-M		Interactions Focus chain G [auth A] Focus chain P [auth B] Interactions & Density Focus chain G [auth A] Focus chain P [auth B]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain K [auth A] SDF format, chain N [auth B] SDF format, chain U [auth B] MOL2 format, chain E [auth A] MOL2 format, chain K [auth A] MOL2 format, chain N [auth B] MOL2 format, chain U [auth B] mmCIF format, chain E [auth A] mmCIF format, chain K [auth A] mmCIF format, chain N [auth B] mmCIF format, chain U [auth B]	E [auth A], K [auth A], N [auth B], U [auth B]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain K [auth A] Focus chain N [auth B] Focus chain U [auth B] Interactions & Density Focus chain E [auth A] Focus chain K [auth A] Focus chain N [auth B] Focus chain U [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.17 ?
R-Value Free: 0.243
R-Value Work: 0.174
R-Value Observed: 0.177
Space Group: C 1 2 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 168.916	α = 90
b = 124.722	β = 91.04
c = 146.195	γ = 90

Software Package:

Software Name	Purpose
HKL-2000	data collection
REFMAC	refinement
HKL-2000	data reduction
HKL-2000	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2010-11-03

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2010-11-03
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2023-11-01
Changes: Data collection, Database references, Derived calculations, Refinement description

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Deposit Data

Help and Resources

3AM9

Complex of bovine xanthine dehydrogenase and trihydroxy FYX-051

FYX-051: A Novel and Potent Hybrid-Type Inhibitor of Xanthine Oxidoreductase

Entity ID: 1

UniProt

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)