6r7d: Difference between revisions

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-'''Unreleased structure'''
-The entry 6r7d is ON HOLD
+==Crystal structure of LTC4S in complex with AZ13690257==
+<StructureSection load='6r7d' size='340' side='right'caption='[[6r7d]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6r7d]] is a 12 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=6R7D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R7D 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]] 2.35&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JUQ:(1~{S},2~{S})-2-[5-[cyclopropylmethyl(naphthalen-1-yl)amino]-4-methoxy-pyrimidin-2-yl]carbonylcyclopropane-1-carboxylic+acid'>JUQ</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</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=6r7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r7d OCA], [https://pdbe.org/6r7d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r7d RCSB], [https://www.ebi.ac.uk/pdbsum/6r7d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r7d ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/LTC4S_HUMAN LTC4S_HUMAN] Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:[https://omim.org/entry/246530 246530]. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.
+== Function ==
+[https://www.uniprot.org/uniprot/LTC4S_HUMAN LTC4S_HUMAN] Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show the cysteine leukotriene cascade remains highly activated in some asthmatics, even those on high dose inhaled or oral corticosteroids. Hence inhibition of LTC4S enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteine leukotriene cascade. Starting from a screening hit 3, a program to discover oral inhibitors of LTC4S led to AZD9898 (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (PBMC IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore stimulated rat model after oral dosing (in vivo IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7, with a human dose predicted to 30 mg q.d.
-Authors:
+Discovery of the Oral Leukotriene-C4 Synthetase Inhibitor (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-met hoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) as a New Treatment for Asthma.,Munck Af Rosenschold M, Johannesson P, Nikitidis A, Tyrchan C, Chang HF, Ronn R, Chapman D, Ullah V, Nikitidis G, Glader P, Kack H, Bonn BK, Wagberg F, Bjorkstrand E, Andersson U, Swedin L, Rohman M, Andreasson T, Lamm Bergstr Ouml M E, Jiang F, Zhou X, Lundqvist A, Malmberg A, Ek ME, Gordon E, Pettersen A, Ripa L, Davis AM J Med Chem. 2019 Aug 15. doi: 10.1021/acs.jmedchem.9b00555. PMID:31415176<ref>PMID:31415176</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6r7d" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Leukotriene C4 synthase|Leukotriene C4 synthase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Ek M]]
+[[Category: Kack H]]