4RX8

SYK Catalytic Domain Complexed with a Potent Triazine Inhibitor2

PDB DOI: https://doi.org/10.2210/pdb4RX8/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2014-12-09 Released: 2015-03-18
Deposition Author(s): Lee, C.C.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.59 ?
R-Value Free: 0.207
R-Value Work: 0.174
R-Value Observed: 0.175

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Discovery and profiling of a selective and efficacious syk inhibitor.

Thoma, G., Smith, A.B., van Eis, M.J., Vangrevelinghe, E., Blanz, J., Aichholz, R., Littlewood-Evans, A., Lee, C.C., Liu, H., Zerwes, H.G.

(2015) J Med Chem 58: 1950-1963

PubMed: 25633741 Search on PubMed
DOI: https://doi.org/10.1021/jm5018863
Primary Citation of Related Structures:
4RX7, 4RX8, 4RX9

PubMed Abstract:
We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.

Organizational Affiliation

Global Discovery Chemistry, ?Analytical Sciences & Imaging, §Autoimmunity, Transplantation and Inflammation Research, Novartis Institutes for Biomedical Research , 4056 Basel, Switzerland.

Macromolecule Content

Total Structure Weight: 34.22 kDa
Atom Count: 2,422
Modelled Residue Count: 269
Deposited Residue Count: 289
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Tyrosine-protein kinase SYK	A	289	Homo sapiens	Mutation(s): 0 Gene Names: SYK EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P43405 (Homo sapiens) Explore P43405 Go to UniProtKB: P43405
PHAROS: P43405 GTEx: ENSG00000165025
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P43405
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
3YX Query on 3YX Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	3-{[(1R,2S)-2-aminocyclohexyl]amino}-5-(1H-indol-7-ylamino)-1,2,4-triazine-6-carboxamide C₁₈ H₂₂ N₈ O FPQNRXITKTZFMF-NWDGAFQWSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain B [auth A] SDF format, chain C [auth A] MOL2 format, chain B [auth A] MOL2 format, chain C [auth A] mmCIF format, chain B [auth A] mmCIF format, chain C [auth A]	B [auth A], C [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Focus chain C [auth A] Interactions & Density Focus chain B [auth A] Focus chain C [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.59 ?
R-Value Free: 0.207
R-Value Work: 0.174
R-Value Observed: 0.175
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 39.955	α = 90
b = 85.333	β = 90
c = 89.53	γ = 90

Software Package:

Software Name	Purpose
DENZO	data reduction
SCALEPACK	data scaling
BUSTER-TNT	refinement
PDB_EXTRACT	data extraction
HKL-2000	data reduction
HKL-2000	data scaling
BUSTER	refinement

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2015-03-18

Deposition Author(s):

Lee, C.C.

Revision History (Full details and data files)

Version 1.0: 2015-03-18
Type: Initial release
Version 1.1: 2017-11-22
Changes: Refinement description
Version 1.2: 2024-02-28
Changes: Data collection, Database references, Derived calculations