6fyv

From Proteopedia

(Difference between revisions)

Current revision

X-RAY STRUCTURE OF CLK4-KD(146-480)/CX-4945 AT 2.46A

Structural highlights

6fyv is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	6fyi, 6fyk, 6fyl, 6fyo, 6fyp, 6fyr
Gene:	CLK4 (HUMAN)
Activity:	Dual-specificity kinase, with EC number 2.7.12.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CLK4_HUMAN] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates SRSF1 and SRSF3. Required for the regulation of alternative splicing of MAPT/TAU. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.^[1] ^[2]

Publication Abstract from PubMed

CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, we report the discovery of a very potent indazole CLK inhibitor series, and the CLK2 X-ray structure of its most potent analog. This new indazole series was identified via a biochemical CLK2 Caliper assay screen with 30k compounds that were selected by an in silico approach. Novel high resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e.g. TG003, CX-4945), are also shown and yield insights into inhibitor selectivity in the CLK family. Efficacy of our new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. We show genotoxicity findings in the human lymphocyte MNT assay using two structurally different CLK inhibitors, which reveals a major concern for pan-CLK inhibition in PMDS.

X-ray structures and feasibility assessment of CLK2 inhibitors for Phelan McDermid syndrome.,Lerchner AM, Kallen J, Bergsdorf C, Arnaud B, Bernhard M, Brichet M, Cobos-Correa A, Elhajouji A, Freuler F, Galimberti I, Guibourdenche C, Haenni S, Holzinger S, Hunziker J, Izaac A, Kaufmann M, Leder L, Martus HJ, von Matt P, Polyakov V, Roethlisberger P, Roma G, Stiefl N, Uteng M ChemMedChem. 2018 Jul 9. doi: 10.1002/cmdc.201800344. PMID:29985556^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Schultz J, Jones T, Bork P, Sheer D, Blencke S, Steyrer S, Wellbrock U, Bevec D, Ullrich A, Wallasch C. Molecular characterization of a cDNA encoding functional human CLK4 kinase and localization to chromosome 5q35 [correction of 4q35]. Genomics. 2001 Feb 1;71(3):368-70. PMID:11170754 doi:http://dx.doi.org/10.1006/geno.2000.6447
↑ Eisenreich A, Bogdanov VY, Zakrzewicz A, Pries A, Antoniak S, Poller W, Schultheiss HP, Rauch U. Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor in human endothelial cells. Circ Res. 2009 Mar 13;104(5):589-99. doi: 10.1161/CIRCRESAHA.108.183905. Epub, 2009 Jan 22. PMID:19168442 doi:10.1161/CIRCRESAHA.108.183905
↑ Lerchner AM, Kallen J, Bergsdorf C, Arnaud B, Bernhard M, Brichet M, Cobos-Correa A, Elhajouji A, Freuler F, Galimberti I, Guibourdenche C, Haenni S, Holzinger S, Hunziker J, Izaac A, Kaufmann M, Leder L, Martus HJ, von Matt P, Polyakov V, Roethlisberger P, Roma G, Stiefl N, Uteng M. X-ray structures and feasibility assessment of CLK2 inhibitors for Phelan McDermid syndrome. ChemMedChem. 2018 Jul 9. doi: 10.1002/cmdc.201800344. PMID:29985556 doi:http://dx.doi.org/10.1002/cmdc.201800344

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6fyv"

@@ Line 3: / Line 3: @@
 <StructureSection load='6fyv' size='340' side='right' caption='[[6fyv]], [[Resolution|resolution]] 2.46&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6fyv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FYV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FYV FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6fyv]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FYV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FYV FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3NG:5-[(3-CHLOROPHENYL)AMINO]BENZO[C][2,6]NAPHTHYRIDINE-8-CARBOXYLIC+ACID'>3NG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6fyi|6fyi]], [[6fyk|6fyk]], [[6fyl|6fyl]], [[6fyo|6fyo]], [[6fyp|6fyp]], [[6fyr|6fyr]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CLK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6fyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fyv OCA], [http://pdbe.org/6fyv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fyv RCSB], [http://www.ebi.ac.uk/pdbsum/6fyv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fyv ProSAT]</span></td></tr>
@@ Line 25: / Line 26: @@
 </StructureSection>
 [[Category: Dual-specificity kinase]]
+[[Category: Human]]
 [[Category: Kallen, J]]
 [[Category: Kinase]]

6fyv

From Proteopedia

Current revision

X-RAY STRUCTURE OF CLK4-KD(146-480)/CX-4945 AT 2.46A

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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