4DFL

Crystal structure of spleen tyrosine kinase complexed with a sulfonamidopyrazine piperidine inhibitor

PDB DOI: https://doi.org/10.2210/pdb4DFL/pdb

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

Deposited: 2012-01-24 Released: 2012-04-25
Deposition Author(s): Lopez, M., Segarra, V., Vidal, B., Wenzkowski, C., Jestel, A., Krapp, S., Blaesse, M., Nagel, S., Schreiner, P.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.98 Å
R-Value Free: 0.243
R-Value Work: 0.196
R-Value Observed: 0.199

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Pyrazine-based Syk kinase inhibitors.

Forns, P., Esteve, C., Taboada, L., Alonso, J.A., Orellana, A., Maldonado, M., Carreno, C., Ramis, I., Lopez, M., Miralpeix, M., Vidal, B.

(2012) Bioorg Med Chem Lett 22: 2784-2788

PubMed: 22425453 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2012.02.087
Primary Citation of Related Structures:
4DFL, 4DFN

PubMed Abstract:
A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.

Organizational Affiliation

Almirall-Barcelona Science Park Unit, Barcelona Science Park, 08028 Barcelona, Spain.

Macromolecule Content

Total Structure Weight: 32.36 kDa
Atom Count: 2,291
Modelled Residue Count: 263
Deposited Residue Count: 274
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	274	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 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
0K0 Query on 0K0 Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	3-amino-6-{3-[(methylsulfonyl)amino]phenyl}-N-(piperidin-4-ylmethyl)pyrazine-2-carboxamide C₁₈ H₂₄ N₆ O₃ S UCJDFWBCXROCMH-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A]	D [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
0K0	Binding MOAD: 4DFL	IC50: 670 (nM) from 1 assay(s)
0K0	PDBBind: 4DFL	IC50: 670 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.98 Å
R-Value Free: 0.243
R-Value Work: 0.196
R-Value Observed: 0.199
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 40.028	α = 90
b = 85.004	β = 90
c = 90.748	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
PDB_EXTRACT	data extraction
XDS	data reduction
XSCALE	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-04-25

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2012-04-25
Type: Initial release
Version 1.1: 2018-04-11
Changes: Advisory, Data collection, Derived calculations, Structure summary
Version 1.2: 2024-02-28
Changes: Advisory, Data collection, Database references, Derived calculations, Structure summary