3S4Q

P38 alpha kinase complexed with a pyrazolo-triazine based inhibitor

PDB DOI: https://doi.org/10.2210/pdb3S4Q/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2011-05-20 Released: 2012-02-01
Deposition Author(s): Sack, J.S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.27 ?
R-Value Free:
0.327 (Depositor), 0.310 (DCC)
R-Value Work:
0.257 (Depositor), 0.280 (DCC)
R-Value Observed:
0.260 (Depositor)

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors.

Dyckman, A.J., Li, T., Pitt, S., Zhang, R., Shen, D.R., McIntyre, K.W., Gillooly, K.M., Shuster, D.J., Doweyko, A.M., Sack, J.S., Kish, K., Kiefer, S.E., Newitt, J.A., Zhang, H., Marathe, P.H., McKinnon, M., Barrish, J.C., Dodd, J.H., Schieven, G.L., Leftheris, K.

(2011) Bioorg Med Chem Lett 21: 4633-4637

PubMed: 21705217 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2011.05.091
Primary Citation of Related Structures:
3S4Q

PubMed Abstract:
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.

Organizational Affiliation

Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543-4000, USA. alaric.dyckman@bms.com

Macromolecule Content

Total Structure Weight: 42.53 kDa
Atom Count: 2,651
Modelled Residue Count: 326
Deposited Residue Count: 366
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Mitogen-activated protein kinase 14	A	366	Homo sapiens	Mutation(s): 0 Gene Names: CSBP, CSBP1, CSBP2, CSPB1, MAPK14, MXI2 EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q16539 (Homo sapiens) Explore Q16539 Go to UniProtKB: Q16539
PHAROS: Q16539 GTEx: ENSG00000112062
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q16539
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NK0 Query on NK0 Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	3-[(6-benzoyl-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]-N-cyclopropyl-4-methylbenzamide C₂₅ H₂₃ N₅ O₂ CQPNJQRTSADQCI-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
NK0	BindingDB: 3S4Q	IC50: 4 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.27 ?
R-Value Free: 0.327 (Depositor), 0.310 (DCC)
R-Value Work: 0.257 (Depositor), 0.280 (DCC)
R-Value Observed: 0.260 (Depositor)

Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 67.34	α = 90
b = 71.5	β = 90
c = 73.49	γ = 90

Software Package:

Software Name	Purpose
BUSTER	refinement
DENZO	data reduction
SCALEPACK	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-02-01

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2012-02-01
Type: Initial release
Version 1.1: 2024-02-28
Changes: Data collection, Database references, Derived calculations

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM157729.