6FT9 | pdb_00006ft9

Crystal structure of CLK1 in complex with inhibitor 16

PDB DOI: https://doi.org/10.2210/pdb6FT9/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2018-02-20 Released: 2018-05-16
Deposition Author(s): Chaikuad, A., Walter, A., von Delft, F., Bountra, C., Arrowsmith, C.H., Edwards, A.M., Kunick, C., Knapp, S., Structural Genomics Consortium (SGC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.87 Å
R-Value Free:
0.202 (Depositor), 0.210 (DCC)
R-Value Work:
0.166 (Depositor), 0.180 (DCC)
R-Value Observed:
0.168 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype.

Walter, A., Chaikuad, A., Helmer, R., Loaec, N., Preu, L., Ott, I., Knapp, S., Meijer, L., Kunick, C.

(2018) PLoS One 13: e0196761-e0196761

PubMed: 29723265 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1371/journal.pone.0196761
Primary Citation of Related Structures:
6FT7, 6FT8, 6FT9

PubMed Abstract:
Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.

Organizational Affiliation

Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Braunschweig, Germany.

Macromolecule Content

Total Structure Weight: 120.77 kDa
Atom Count: 9,019
Modelled Residue Count: 1,010
Deposited Residue Count: 1,017
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Dual specificity protein kinase CLK1	A, B, C	339	Homo sapiens	Mutation(s): 1 Gene Names: CLK1, CLK EC: 2.7.12.1
UniProt & NIH Common Fund Data Resources
Find proteins for P49759 (Homo sapiens) Explore P49759 Go to UniProtKB: P49759
PHAROS: P49759 GTEx: ENSG00000013441
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P49759
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
E6W Query on E6W Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain K [auth B] SDF format, chain P [auth C] MOL2 format, chain D [auth A] MOL2 format, chain K [auth B] MOL2 format, chain P [auth C] mmCIF format, chain D [auth A] mmCIF format, chain K [auth B] mmCIF format, chain P [auth C]	D [auth A], K [auth B], P [auth C]	2-bromanyl-3-phenyl-1~{H}-pyrrolo[3,4-g]indol-8-one C₁₆ H₉ Br N₂ O VKVBXHZFKDKMDA-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain K [auth B] Focus chain P [auth C] Interactions & Density Focus chain D [auth A] Focus chain K [auth B] Focus chain P [auth C]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain M [auth B] SDF format, chain R [auth C] MOL2 format, chain F [auth A] MOL2 format, chain M [auth B] MOL2 format, chain R [auth C] mmCIF format, chain F [auth A] mmCIF format, chain M [auth B] mmCIF format, chain R [auth C]	F [auth A], M [auth B], R [auth C]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain F [auth A] Focus chain M [auth B] Focus chain R [auth C] Interactions & Density Focus chain F [auth A] Focus chain M [auth B] Focus chain R [auth C]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain J [auth A] SDF format, chain N [auth B] SDF format, chain S [auth C] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain J [auth A] MOL2 format, chain N [auth B] MOL2 format, chain S [auth C] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain J [auth A] mmCIF format, chain N [auth B] mmCIF format, chain S [auth C]	G [auth A], H [auth A], J [auth A], N [auth B], S [auth C]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain H [auth A] Focus chain J [auth A] Focus chain N [auth B] Focus chain S [auth C] Interactions & Density Focus chain G [auth A] Focus chain H [auth A] Focus chain J [auth A] Focus chain N [auth B] Focus chain S [auth C]
BR Query on BR Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain L [auth B] SDF format, chain Q [auth C] MOL2 format, chain E [auth A] MOL2 format, chain L [auth B] MOL2 format, chain Q [auth C] mmCIF format, chain E [auth A] mmCIF format, chain L [auth B] mmCIF format, chain Q [auth C]	E [auth A], L [auth B], Q [auth C]	BROMIDE ION Br CPELXLSAUQHCOX-UHFFFAOYSA-M		Interactions Focus chain E [auth A] Focus chain L [auth B] Focus chain Q [auth C] Interactions & Density Focus chain E [auth A] Focus chain L [auth B] Focus chain Q [auth C]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain O [auth B] SDF format, chain T [auth C] MOL2 format, chain I [auth A] MOL2 format, chain O [auth B] MOL2 format, chain T [auth C] mmCIF format, chain I [auth A] mmCIF format, chain O [auth B] mmCIF format, chain T [auth C]	I [auth A], O [auth B], T [auth C]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain O [auth B] Focus chain T [auth C] Interactions & Density Focus chain I [auth A] Focus chain O [auth B] Focus chain T [auth C]