5QJ2

CRYSTAL STRUCTURE OF MYELOPEROXIDASE SUBFORM C (MPO) OMPLEX WITH COMPOUND-20 AKA 7-((3-(1-METHYL-1H-PYRAZOL-3- YL)BENZYL)OXY)- 1H-[1,2,3]TRIAZOLO[4,5-B]PYRIDIN-5-AMINE

PDB DOI: https://doi.org/10.2210/pdb5QJ2/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: 2.82 Å
R-Value Free: 0.272
R-Value Work: 0.206
R-Value Observed: 0.210

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 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: 272.4 kDa
Atom Count: 18,513
Modelled Residue Count: 2,272
Deposited Residue Count: 2,288
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], E [auth F], G [auth H]	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], F [auth G], H [auth I]	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
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 8 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
HEM Query on HEM Download Ideal Coordinates CCD File SDF format, chain FA [auth E] SDF format, chain FB [auth I] SDF format, chain OA [auth G] SDF format, chain P [auth B] MOL2 format, chain FA [auth E] MOL2 format, chain FB [auth I] MOL2 format, chain OA [auth G] MOL2 format, chain P [auth B] mmCIF format, chain FA [auth E] mmCIF format, chain FB [auth I] mmCIF format, chain OA [auth G] mmCIF format, chain P [auth B]	FA [auth E], FB [auth I], OA [auth G], P [auth B]	PROTOPORPHYRIN IX CONTAINING FE C₃₄ H₃₂ Fe N₄ O₄ KABFMIBPWCXCRK-RGGAHWMASA-L		Interactions Focus chain FA [auth E] Focus chain FB [auth I] Focus chain OA [auth G] Focus chain P [auth B] Interactions & Density Focus chain FA [auth E] Focus chain FB [auth I] Focus chain OA [auth G] Focus chain P [auth B]
JXS Query on JXS Download Ideal Coordinates CCD File SDF format, chain GA [auth E] SDF format, chain TA [auth G] SDF format, chain U [auth B] MOL2 format, chain GA [auth E] MOL2 format, chain TA [auth G] MOL2 format, chain U [auth B] mmCIF format, chain GA [auth E] mmCIF format, chain TA [auth G] mmCIF format, chain U [auth B]	GA [auth E], TA [auth G], U [auth B]	7-{[3-(1-methyl-1H-pyrazol-3-yl)phenyl]methoxy}-1H-[1,2,3]triazolo[4,5-b]pyridin-5-amine C₁₆ H₁₅ N₇ O WGMJNFFLMIILAZ-UHFFFAOYSA-N		Interactions Focus chain GA [auth E] Focus chain TA [auth G] Focus chain U [auth B] Interactions & Density Focus chain GA [auth E] Focus chain TA [auth G] Focus chain U [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain AA [auth E] SDF format, chain AB [auth I] SDF format, chain BA [auth E] SDF format, chain BB [auth I] SDF format, chain CA [auth E] SDF format, chain CB [auth I] SDF format, chain DA [auth E] SDF format, chain DB [auth I] SDF format, chain I [auth B] SDF format, chain IA [auth G] SDF format, chain J [auth B] SDF format, chain JA [auth G] SDF format, chain K [auth B] SDF format, chain KA [auth G] SDF format, chain L [auth B] SDF format, chain LA [auth G] SDF format, chain M [auth B] SDF format, chain NA [auth G] SDF format, chain O [auth B] SDF format, chain PA [auth G] SDF format, chain Q [auth B] SDF format, chain WA [auth I] MOL2 format, chain AA [auth E] MOL2 format, chain AB [auth I] MOL2 format, chain BA [auth E] MOL2 format, chain BB [auth I] MOL2 format, chain CA [auth E] MOL2 format, chain CB [auth I] MOL2 format, chain DA [auth E] MOL2 format, chain DB [auth I] MOL2 format, chain I [auth B] MOL2 format, chain IA [auth G] MOL2 format, chain J [auth B] MOL2 format, chain JA [auth G] MOL2 format, chain K [auth B] MOL2 format, chain KA [auth G] MOL2 format, chain L [auth B] MOL2 format, chain LA [auth G] MOL2 format, chain M [auth B] MOL2 format, chain NA [auth G] MOL2 format, chain O [auth B] MOL2 format, chain PA [auth G] MOL2 format, chain Q [auth B] MOL2 format, chain WA [auth I] mmCIF format, chain AA [auth E] mmCIF format, chain AB [auth I] mmCIF format, chain BA [auth E] mmCIF format, chain BB [auth I] mmCIF format, chain CA [auth E] mmCIF format, chain CB [auth I] mmCIF format, chain DA [auth E] mmCIF format, chain DB [auth I] mmCIF format, chain I [auth B] mmCIF format, chain IA [auth G] mmCIF format, chain J [auth B] mmCIF format, chain JA [auth G] mmCIF format, chain K [auth B] mmCIF format, chain KA [auth G] mmCIF format, chain L [auth B] mmCIF format, chain LA [auth G] mmCIF format, chain M [auth B] mmCIF format, chain NA [auth G] mmCIF format, chain O [auth B] mmCIF format, chain PA [auth G] mmCIF format, chain Q [auth B] mmCIF format, chain WA [auth I]	AA [auth E] AB [auth I] BA [auth E] BB [auth I] CA [auth E] AA [auth E], AB [auth I], BA [auth E], BB [auth I], CA [auth E], CB [auth I], DA [auth E], DB [auth I], I [auth B], IA [auth G], J [auth B], JA [auth G], K [auth B], KA [auth G], L [auth B], LA [auth G], M [auth B], NA [auth G], O [auth B], PA [auth G], Q [auth B], WA [auth I]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain AA [auth E] Focus chain AB [auth I] Focus chain BA [auth E] Focus chain BB [auth I] Focus chain CA [auth E] Focus chain CB [auth I] Focus chain DA [auth E] Focus chain DB [auth I] Focus chain I [auth B] Focus chain IA [auth G] Focus chain J [auth B] Focus chain JA [auth G] Focus chain K [auth B] Focus chain KA [auth G] Focus chain L [auth B] Focus chain LA [auth G] Focus chain M [auth B] Focus chain NA [auth G] Focus chain O [auth B] Focus chain PA [auth G] Focus chain Q [auth B] Focus chain WA [auth I] Interactions & Density Focus chain AA [auth E] Focus chain AB [auth I] Focus chain BA [auth E] Focus chain BB [auth I] Focus chain CA [auth E] Focus chain CB [auth I] Focus chain DA [auth E] Focus chain DB [auth I] Focus chain I [auth B] Focus chain IA [auth G] Focus chain J [auth B] Focus chain JA [auth G] Focus chain K [auth B] Focus chain KA [auth G] Focus chain L [auth B] Focus chain LA [auth G] Focus chain M [auth B] Focus chain NA [auth G] Focus chain O [auth B] Focus chain PA [auth G] Focus chain Q [auth B] Focus chain WA [auth I]
MAN Query on MAN Download Ideal Coordinates CCD File SDF format, chain RA [auth G] SDF format, chain S [auth B] SDF format, chain SA [auth G] SDF format, chain T [auth B] SDF format, chain Y [auth E] SDF format, chain Z [auth E] SDF format, chain ZA [auth I] SDF format, chain YA [auth I] MOL2 format, chain RA [auth G] MOL2 format, chain S [auth B] MOL2 format, chain SA [auth G] MOL2 format, chain T [auth B] MOL2 format, chain Y [auth E] MOL2 format, chain Z [auth E] MOL2 format, chain ZA [auth I] MOL2 format, chain YA [auth I] mmCIF format, chain RA [auth G] mmCIF format, chain S [auth B] mmCIF format, chain SA [auth G] mmCIF format, chain T [auth B] mmCIF format, chain Y [auth E] mmCIF format, chain Z [auth E] mmCIF format, chain ZA [auth I] mmCIF format, chain YA [auth I]	RA [auth G] S [auth B] SA [auth G] T [auth B] Y [auth E] RA [auth G], S [auth B], SA [auth G], T [auth B], Y [auth E], YA [auth I], Z [auth E], ZA [auth I]	alpha-D-mannopyranose C₆ H₁₂ O₆ WQZGKKKJIJFFOK-PQMKYFCFSA-N		Interactions Focus chain RA [auth G] Focus chain S [auth B] Focus chain SA [auth G] Focus chain T [auth B] Focus chain Y [auth E] Focus chain YA [auth I] Focus chain Z [auth E] Focus chain ZA [auth I] Interactions & Density Focus chain RA [auth G] Focus chain S [auth B] Focus chain SA [auth G] Focus chain T [auth B] Focus chain Y [auth E] Focus chain YA [auth I] Focus chain Z [auth E] Focus chain ZA [auth I]
BMA Query on BMA Download Ideal Coordinates CCD File SDF format, chain QA [auth G] SDF format, chain R [auth B] SDF format, chain X [auth E] SDF format, chain XA [auth I] MOL2 format, chain QA [auth G] MOL2 format, chain R [auth B] MOL2 format, chain X [auth E] MOL2 format, chain XA [auth I] mmCIF format, chain QA [auth G] mmCIF format, chain R [auth B] mmCIF format, chain X [auth E] mmCIF format, chain XA [auth I]	QA [auth G], R [auth B], X [auth E], XA [auth I]	beta-D-mannopyranose C₆ H₁₂ O₆ WQZGKKKJIJFFOK-RWOPYEJCSA-N		Interactions Focus chain QA [auth G] Focus chain R [auth B] Focus chain X [auth E] Focus chain XA [auth I] Interactions & Density Focus chain QA [auth G] Focus chain R [auth B] Focus chain X [auth E] Focus chain XA [auth I]
FUC Query on FUC Download Ideal Coordinates CCD File SDF format, chain EA [auth E] SDF format, chain EB [auth I] SDF format, chain MA [auth G] SDF format, chain N [auth B] MOL2 format, chain EA [auth E] MOL2 format, chain EB [auth I] MOL2 format, chain MA [auth G] MOL2 format, chain N [auth B] mmCIF format, chain EA [auth E] mmCIF format, chain EB [auth I] mmCIF format, chain MA [auth G] mmCIF format, chain N [auth B]	EA [auth E], EB [auth I], MA [auth G], N [auth B]	alpha-L-fucopyranose C₆ H₁₂ O₅ SHZGCJCMOBCMKK-SXUWKVJYSA-N		Interactions Focus chain EA [auth E] Focus chain EB [auth I] Focus chain MA [auth G] Focus chain N [auth B] Interactions & Density Focus chain EA [auth E] Focus chain EB [auth I] Focus chain MA [auth G] Focus chain N [auth B]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain GB [auth I] SDF format, chain HA [auth E] SDF format, chain UA [auth G] SDF format, chain V [auth B] MOL2 format, chain GB [auth I] MOL2 format, chain HA [auth E] MOL2 format, chain UA [auth G] MOL2 format, chain V [auth B] mmCIF format, chain GB [auth I] mmCIF format, chain HA [auth E] mmCIF format, chain UA [auth G] mmCIF format, chain V [auth B]	GB [auth I], HA [auth E], UA [auth G], V [auth B]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain GB [auth I] Focus chain HA [auth E] Focus chain UA [auth G] Focus chain V [auth B] Interactions & Density Focus chain GB [auth I] Focus chain HA [auth E] Focus chain UA [auth G] Focus chain V [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain VA [auth G] SDF format, chain W [auth B] MOL2 format, chain VA [auth G] MOL2 format, chain W [auth B] mmCIF format, chain VA [auth G] mmCIF format, chain W [auth B]	VA [auth G], W [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain VA [auth G] Focus chain W [auth B] Interactions & Density Focus chain VA [auth G] Focus chain W [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.82 Å
R-Value Free: 0.272
R-Value Work: 0.206
R-Value Observed: 0.210
Space Group: C 2 2 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 143.817	α = 90
b = 150.949	β = 90
c = 233.104	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 1.1: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Data collection, Derived calculations, Structure summary
Version 1.2: 2021-05-12
Changes: Structure summary
Version 1.3: 2024-10-09
Changes: Advisory, Data collection, Database references, Structure summary