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==Salt-Inducible Kinase 3 in complex with an inhibitor==
<StructureSection load='8oku' size='340' side='right'caption='[[8oku]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8oku]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OKU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OKU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VRU:~{N}-ethyl-4-[5-[1-(2-hydroxyethyl)pyrazol-4-yl]benzimidazol-1-yl]-2,6-dimethoxy-benzamide'>VRU</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8oku FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8oku OCA], [https://pdbe.org/8oku PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8oku RCSB], [https://www.ebi.ac.uk/pdbsum/8oku PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8oku ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SIK3_HUMAN SIK3_HUMAN] The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/SIK3_HUMAN SIK3_HUMAN] Positive regulator of mTOR signaling that functions by triggering the degradation of DEPTOR, an mTOR inhibitor. Involved in the dynamic regulation of mTOR signaling in chondrocyte differentiation during skeletogenesis (PubMed:30232230). Negatively regulates cAMP signaling pathway possibly by acting on CRTC2/TORC2 and CRTC3/TORC3 (Probable). Prevents HDAC4 translocation to the nucleus (By similarity).[UniProtKB:Q6P4S6]<ref>PMID:30232230</ref> <ref>PMID:29211348</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 are serine/threonine kinases and form a subfamily of the protein kinase AMP-activated protein kinase (AMPK) family. Inhibition of SIKs in stimulated innate immune cells and mouse models has been associated with a dual mechanism of action consisting of a reduction of pro-inflammatory cytokines and an increase of immunoregulatory cytokine production, suggesting a therapeutic potential for inflammatory diseases. Following a high-throughput screening campaign, subsequent hit to lead optimization through synthesis, structure-activity relationship, kinome selectivity, and pharmacokinetic investigations led to the discovery of clinical candidate GLPG3312 (compound 28), a potent and selective pan-SIK inhibitor (IC(50): 2.0 nM for SIK1, 0.7 nM for SIK2, and 0.6 nM for SIK3). Characterization of the first human SIK3 crystal structure provided an understanding of the binding mode and kinome selectivity of the chemical series. GLPG3312 demonstrated both anti-inflammatory and immunoregulatory activities in vitro in human primary myeloid cells and in vivo in mouse models.

Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312.,Temal-Laib T, Peixoto C, Desroy N, De Lemos E, Bonnaterre F, Bienvenu N, Picolet O, Sartori E, Bucher D, Lopez-Ramos M, Roca Magadan C, Laenen W, Flower T, Mollat P, Bugaud O, Touitou R, Pereira Fernandes A, Lavazais S, Monjardet A, Borgonovi M, Gosmini R, Brys R, Amantini D, De Vos S, Andrews M J Med Chem. 2023 Dec 26. doi: 10.1021/acs.jmedchem.3c01428. PMID:38147525<ref>PMID:38147525</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8oku" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Flower TG]]
[[Category: Lamers MBAC]]
[[Category: Leonard PM]]
[[Category: Mollat P]]