6FT7 | pdb_00006ft7

Crystal structure of CLK3 in complex with compound 8a

PDB DOI: https://doi.org/10.2210/pdb6FT7/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

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: 2.02 Å
R-Value Free:
0.235 (Depositor), 0.240 (DCC)
R-Value Work:
0.192 (Depositor), 0.200 (DCC)
R-Value Observed:
0.194 (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: 87.65 kDa
Atom Count: 6,481
Modelled Residue Count: 712
Deposited Residue Count: 720
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 CLK3	A, B	360	Homo sapiens	Mutation(s): 0 Gene Names: CLK3 EC: 2.7.12.1
UniProt & NIH Common Fund Data Resources
Find proteins for P49761 (Homo sapiens) Explore P49761 Go to UniProtKB: P49761
PHAROS: P49761 GTEx: ENSG00000179335
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P49761
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
E6Q Query on E6Q Download Ideal Coordinates CCD File SDF format, chain DA [auth B] SDF format, chain M [auth A] MOL2 format, chain DA [auth B] MOL2 format, chain M [auth A] mmCIF format, chain DA [auth B] mmCIF format, chain M [auth A]	DA [auth B], M [auth A]	3-phenyl-1~{H}-pyrrolo[3,4-g]indol-8-one C₁₆ H₁₀ N₂ O YJGNZVVUIPDSRL-UHFFFAOYSA-N		Interactions Focus chain DA [auth B] Focus chain M [auth A] Interactions & Density Focus chain DA [auth B] Focus chain M [auth A]
IOD Query on IOD Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain P [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain P [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain P [auth B]	C [auth A] D [auth A] E [auth A] F [auth A] G [auth A] C [auth A], D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], N [auth B], O [auth B], P [auth B], Q [auth B], R [auth B], S [auth B], T [auth B]	IODIDE ION I XMBWDFGMSWQBCA-UHFFFAOYSA-M		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain AA [auth B] SDF format, chain BA [auth B] SDF format, chain CA [auth B] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain U [auth B] SDF format, chain V [auth B] SDF format, chain W [auth B] SDF format, chain X [auth B] SDF format, chain Y [auth B] SDF format, chain Z [auth B] MOL2 format, chain AA [auth B] MOL2 format, chain BA [auth B] MOL2 format, chain CA [auth B] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain U [auth B] MOL2 format, chain V [auth B] MOL2 format, chain W [auth B] MOL2 format, chain X [auth B] MOL2 format, chain Y [auth B] MOL2 format, chain Z [auth B] mmCIF format, chain AA [auth B] mmCIF format, chain BA [auth B] mmCIF format, chain CA [auth B] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain U [auth B] mmCIF format, chain V [auth B] mmCIF format, chain W [auth B] mmCIF format, chain X [auth B] mmCIF format, chain Y [auth B] mmCIF format, chain Z [auth B]	AA [auth B] BA [auth B] CA [auth B] J [auth A] K [auth A] AA [auth B], BA [auth B], CA [auth B], J [auth A], K [auth A], L [auth A], U [auth B], V [auth B], W [auth B], X [auth B], Y [auth B], Z [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain AA [auth B] Focus chain BA [auth B] Focus chain CA [auth B] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain U [auth B] Focus chain V [auth B] Focus chain W [auth B] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B] Interactions & Density Focus chain AA [auth B] Focus chain BA [auth B] Focus chain CA [auth B] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain U [auth B] Focus chain V [auth B] Focus chain W [auth B] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B]