6t8v: Difference between revisions
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The | ==Complement factor B in complex with (S)-5,7-Dimethyl-4-((2-phenylpiperidin-1-yl)methyl)-1H-indole== | ||
<StructureSection load='6t8v' size='340' side='right'caption='[[6t8v]], [[Resolution|resolution]] 2.29Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6t8v]] 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=6T8V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T8V 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]] 2.29Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MVK:4-[(2~{S})-1-[(5,7-dimethyl-1~{H}-indol-4-yl)methyl]piperidin-2-yl]benzoic+acid'>MVK</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6t8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t8v OCA], [https://pdbe.org/6t8v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t8v RCSB], [https://www.ebi.ac.uk/pdbsum/6t8v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t8v ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/CFAB_HUMAN CFAB_HUMAN] Defects in CFB are a cause of susceptibility to hemolytic uremic syndrome atypical type 4 (AHUS4) [MIM:[https://omim.org/entry/612924 612924]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:17182750</ref> <ref>PMID:20513133</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CFAB_HUMAN CFAB_HUMAN] Factor B which is part of the alternate pathway of the complement system is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate the C3 or C5 convertase. It has also been implicated in proliferation and differentiation of preactivated B-lymphocytes, rapid spreading of peripheral blood monocytes, stimulation of lymphocyte blastogenesis and lysis of erythrocytes. Ba inhibits the proliferation of preactivated B-lymphocytes. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications. | |||
Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)be nzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases.,Mainolfi N, Ehara T, Karki RG, Anderson K, Mac Sweeney A, Liao SM, Argikar UA, Jendza K, Zhang C, Powers J, Klosowski DW, Crowley M, Kawanami T, Ding J, April M, Forster C, Serrano-Wu M, Capparelli M, Ramqaj R, Solovay C, Cumin F, Smith TM, Ferrara L, Lee W, Long D, Prentiss M, De Erkenez A, Yang L, Liu F, Sellner H, Sirockin F, Valeur E, Erbel P, Ostermeier D, Ramage P, Gerhartz B, Schubart A, Flohr S, Gradoux N, Feifel R, Vogg B, Wiesmann C, Maibaum J, Eder J, Sedrani R, Harrison RA, Mogi M, Jaffee BD, Adams CM J Med Chem. 2020 Feb 19. doi: 10.1021/acs.jmedchem.9b01870. PMID:32073845<ref>PMID:32073845</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6t8v" style="background-color:#fffaf0;"></div> | ||
[[Category: Adams | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Adams C]] | ||
[[Category: | [[Category: Adams CM]] | ||
[[Category: | [[Category: Anderson K]] | ||
[[Category: | [[Category: April M]] | ||
[[Category: | [[Category: Argikar UA]] | ||
[[Category: | [[Category: Capparelli M]] | ||
[[Category: | [[Category: Crowley M]] | ||
[[Category: | [[Category: Cumin F]] | ||
[[Category: | [[Category: De Erkenez A]] | ||
[[Category: | [[Category: Ding J]] | ||
[[Category: | [[Category: Eder J]] | ||
[[Category: | [[Category: Ehara T]] | ||
[[Category: | [[Category: Erbel P]] | ||
[[Category: | [[Category: Fang L]] | ||
[[Category: | [[Category: Feifel R]] | ||
[[Category: | [[Category: Ferrara L]] | ||
[[Category: | [[Category: Flohr S]] | ||
[[Category: | [[Category: Forster C]] | ||
[[Category: | [[Category: Gerhartz B]] | ||
[[Category: | [[Category: Gradoux N]] | ||
[[Category: | [[Category: Harrison RA]] | ||
[[Category: | [[Category: Jaffee BD]] | ||
[[Category: Long | [[Category: Jendza K]] | ||
[[Category: | [[Category: Karki RG]] | ||
[[Category: Mainolfi | [[Category: Kawanami T]] | ||
[[Category: | [[Category: Klosowski DW]] | ||
[[Category: | [[Category: Lee W]] | ||
[[Category: | [[Category: Liao S-M]] | ||
[[Category: Ramage | [[Category: Long D]] | ||
[[Category: | [[Category: Mac Sweeney A]] | ||
[[Category: | [[Category: Maibaum J]] | ||
[[Category: | [[Category: Mainolfi N]] | ||
[[Category: | [[Category: Mogi M]] | ||
[[Category: Serrano-Wu | [[Category: Powers J]] | ||
[[Category: | [[Category: Prentiss M]] | ||
[[Category: | [[Category: Ramage P]] | ||
[[Category: | [[Category: Ramqaj R]] | ||
[[Category: | [[Category: Schubart A]] | ||
[[Category: | [[Category: Sedrani R]] | ||
[[Category: | [[Category: Sellner H]] | ||
[[Category: | [[Category: Serrano-Wu M]] | ||
[[Category: | [[Category: Sirockin F]] | ||
[[Category: Smith TM]] | |||
[[Category: Solovay C]] | |||
[[Category: Valeur E]] | |||
[[Category: Vogg B]] | |||
[[Category: Wiesmann C]] | |||
[[Category: Yang L]] | |||
[[Category: Zhang C]] | |||