5QJ3

CRYSTAL STRUCTURE OF MYELOPEROXIDASE SUBFORM C (MPO) COMPLEX WITH COMPOUND-24 AKA 7-({4-CHLORO-3'-FLUORO-[1,1'- BIPHENYL]-3-YL}METHOXY)-3H-[1,2,3]TRIAZOLO[4,5-B]PYRIDIN- 5-AMINE

PDB DOI: https://doi.org/10.2210/pdb5QJ3/pdb
Deposition Group: G_1002056 ExploreG_1002056

Classification: METAL BINDING PROTEIN
Organism(s): Homo sapiens
Expression System: Homo sapiens
Mutation(s): No

Deposited: 2018-09-26 Released: 2019-02-06
Deposition Author(s): Khan, J.A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.76 Å
R-Value Free: 0.228
R-Value Work: 0.184
R-Value Observed: 0.186

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Potent Triazolopyridine Myeloperoxidase Inhibitors.

Wurtz, N.R., Viet, A., Shaw, S.A., Dilger, A., Valente, M.N., Khan, J.A., Jusuf, S., Narayanan, R., Fernando, G., Lo, F., Liu, X., Locke, G.A., Kopcho, L., Abell, L.M., Sleph, P., Basso, M., Zhao, L., Wexler, R.R., Duclos, F., Kick, E.K.

(2018) ACS Med Chem Lett 9: 1175-1180

PubMed: 30613322 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.8b00308
Primary Citation of Related Structures:
5QJ2, 5QJ3

PubMed Abstract:
Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain. Crystal structures of inhibitors bound to the MPO active site demonstrated alternate binding modes and guided rational design of MPO inhibitors. Thioether 36 showed significant inhibition of MPO activity in an acute mouse inflammation model after oral dosing.

Organizational Affiliation

Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States.

Macromolecule Content

Total Structure Weight: 135.69 kDa
Atom Count: 9,480
Modelled Residue Count: 1,135
Deposited Residue Count: 1,144
Unique protein chains: 2

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Myeloperoxidase	A, C [auth D]	105	Homo sapiens	Mutation(s): 0 EC: 1.11.2.2
UniProt & NIH Common Fund Data Resources
Find proteins for P05164 (Homo sapiens) Explore P05164 Go to UniProtKB: P05164
PHAROS: P05164 GTEx: ENSG00000005381
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P05164
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Myeloperoxidase	B, D [auth E]	467	Homo sapiens	Mutation(s): 0 EC: 1.11.2.2
UniProt & NIH Common Fund Data Resources
Find proteins for P05164 (Homo sapiens) Explore P05164 Go to UniProtKB: P05164
PHAROS: P05164 GTEx: ENSG00000005381
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P05164
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain B	Go to GlyGen: P05164-1
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

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	E [auth C], G	2		N/A	Interactions Focus chain E [auth C] Focus chain G Interactions & Density Focus chain E [auth C] Focus chain G
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Entity ID: 4
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose	F, H	6		N/A	Interactions Focus chain F Focus chain H Interactions & Density Focus chain F Focus chain H
Glycosylation Resources
GlyTouCan: G82348BZ GlyCosmos: G82348BZ GlyGen: G82348BZ

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
HEM Query on HEM Download Ideal Coordinates CCD File SDF format, chain J [auth B] SDF format, chain O [auth E] MOL2 format, chain J [auth B] MOL2 format, chain O [auth E] mmCIF format, chain J [auth B] mmCIF format, chain O [auth E]	J [auth B], O [auth E]	PROTOPORPHYRIN IX CONTAINING FE C₃₄ H₃₂ Fe N₄ O₄ KABFMIBPWCXCRK-RGGAHWMASA-L		Interactions Focus chain J [auth B] Focus chain O [auth E] Interactions & Density Focus chain J [auth B] Focus chain O [auth E]
JXP Query on JXP Download Ideal Coordinates CCD File SDF format, chain N [auth B] MOL2 format, chain N [auth B] mmCIF format, chain N [auth B]	N [auth B]	7-[(4-chloro-3'-fluoro[1,1'-biphenyl]-3-yl)methoxy]-1H-[1,2,3]triazolo[4,5-b]pyridin-5-amine C₁₈ H₁₃ Cl F N₅ O ZMHGTFZMJCIDLN-UHFFFAOYSA-N		Interactions Focus chain N [auth B] Interactions & Density Focus chain N [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain K [auth B] SDF format, chain P [auth E] MOL2 format, chain K [auth B] MOL2 format, chain P [auth E] mmCIF format, chain K [auth B] mmCIF format, chain P [auth E]	K [auth B], P [auth E]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain K [auth B] Focus chain P [auth E] Interactions & Density Focus chain K [auth B] Focus chain P [auth E]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain L [auth B] SDF format, chain Q [auth E] MOL2 format, chain L [auth B] MOL2 format, chain Q [auth E] mmCIF format, chain L [auth B] mmCIF format, chain Q [auth E]	L [auth B], Q [auth E]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain L [auth B] Focus chain Q [auth E] Interactions & Density Focus chain L [auth B] Focus chain Q [auth E]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain M [auth B] MOL2 format, chain I [auth A] MOL2 format, chain M [auth B] mmCIF format, chain I [auth A] mmCIF format, chain M [auth B]	I [auth A], M [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain I [auth A] Focus chain M [auth B] Interactions & Density Focus chain I [auth A] Focus chain M [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.76 Å
R-Value Free: 0.228
R-Value Work: 0.184
R-Value Observed: 0.186
Space Group: P 4₃ 2₁ 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 106.541	α = 90
b = 106.541	β = 90
c = 238.694	γ = 90

Software Package:

Software Name	Purpose
XDS	data reduction
SCALA	data scaling
PHASER	phasing
BUSTER	refinement
PDB_EXTRACT	data extraction

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2019-02-06

Deposition Author(s):

Khan, J.A.

Revision History (Full details and data files)

Version 1.0: 2019-02-06
Type: Initial release
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
Version 2.1: 2021-05-12
Changes: Derived calculations, Structure summary
Version 2.2: 2024-10-30
Changes: Advisory, Data collection, Database references, Structure summary