View source for 7lgk


==Crystal structure of soluble guanylate cyclase activator runcaciguat (BAY 1101042) bound to nostoc H-NOX domain==
<StructureSection load='7lgk' size='340' side='right'caption='[[7lgk]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7lgk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Nostoc_sp._PCC_7120_=_FACHB-418 Nostoc sp. PCC 7120 = FACHB-418]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LGK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LGK 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]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XZ7:Runcaciguat'>XZ7</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=7lgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lgk OCA], [https://pdbe.org/7lgk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lgk RCSB], [https://www.ebi.ac.uk/pdbsum/7lgk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lgk ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q8YUQ7_NOSS1 Q8YUQ7_NOSS1] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Herein we describe the discovery, mode of action, and preclinical characterization of the soluble guanylate cyclase (sGC) activator runcaciguat. The sGC enzyme, via the formation of cyclic guanosine monophoshphate, is a key regulator of body and tissue homeostasis. sGC activators with their unique mode of action are activating the oxidized and heme-free and therefore NO-unresponsive form of sGC, which is formed under oxidative stress. The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. We overcame limitations of first-generation sGC activators and identified a new chemical class via high-throughput screening. The investigation of the structure-activity relationship allowed to improve potency and multiple solubility, permeability, metabolism, and drug-drug interactions parameters. This program resulted in the discovery of the oral sGC activator runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy.

Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042).,Hahn MG, Lampe T, El Sheikh S, Griebenow N, Woltering E, Schlemmer KH, Dietz L, Gerisch M, Wunder F, Becker-Pelster EM, Mondritzki T, Tinel H, Knorr A, Kern A, Lang D, Hueser J, Schomber T, Benardeau A, Eitner F, Truebel H, Mittendorf J, Kumar V, van den Akker F, Schaefer M, Geiss V, Sandner P, Stasch JP J Med Chem. 2021 Apr 19. doi: 10.1021/acs.jmedchem.0c02154. PMID:33872507<ref>PMID:33872507</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7lgk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Nostoc sp. PCC 7120 = FACHB-418]]
[[Category: Kumar V]]
[[Category: Schaefer M]]
[[Category: Van den Akker F]]