View source for 6qsw


==Complement factor B protease domain in complex with the reversible inhibitor N-(2-bromo-4-methylnaphthalen-1-yl)-4,5-dihydro-1H-imidazol-2-amine.==
<StructureSection load='6qsw' size='340' side='right'caption='[[6qsw]], [[Resolution|resolution]] 1.64&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6qsw]] is a 3 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=6QSW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QSW 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]] 1.64&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JGT:~{N}-(2-bromanyl-4-methyl-naphthalen-1-yl)-4,5-dihydro-1~{H}-imidazol-2-amine'>JGT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6qsw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qsw OCA], [https://pdbe.org/6qsw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qsw RCSB], [https://www.ebi.ac.uk/pdbsum/6qsw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qsw 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 ==
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead to complement-driven nephropathies. Here we describe the discovery of a highly potent, reversible, and selective small-molecule inhibitor of factor B, a serine protease that drives the central amplification loop of the AP. Oral administration of the inhibitor prevents KRN-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous nephropathy in rats. In addition, inhibition of factor B prevents complement activation in sera from C3 glomerulopathy patients and the hemolysis of human PNH erythrocytes. These data demonstrate the potential therapeutic value of using a factor B inhibitor for systemic treatment of complement-mediated diseases and provide a basis for its clinical development.

Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.,Schubart A, Anderson K, Mainolfi N, Sellner H, Ehara T, Adams CM, Mac Sweeney A, Liao SM, Crowley M, Littlewood-Evans A, Sarret S, Wieczorek G, Perrot L, Dubost V, Flandre T, Zhang Y, Smith RJH, Risitano AM, Karki RG, Zhang C, Valeur E, Sirockin F, Gerhartz B, Erbel P, Hughes N, Smith TM, Cumin F, Argikar UA, Haraldsson B, Mogi M, Sedrani R, Wiesmann C, Jaffee B, Maibaum J, Flohr S, Harrison R, Eder J Proc Natl Acad Sci U S A. 2019 Mar 29. pii: 1820892116. doi:, 10.1073/pnas.1820892116. PMID:30926668<ref>PMID:30926668</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6qsw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Adams CM]]
[[Category: Anderson K]]
[[Category: Argikar U]]
[[Category: Crowley M]]
[[Category: Cumin F]]
[[Category: Eder J]]
[[Category: Ehara T]]
[[Category: Erbel P]]
[[Category: Flohr S]]
[[Category: Gerhartz B]]
[[Category: Harrison R]]
[[Category: Hughes N]]
[[Category: Jaffee B]]
[[Category: Karki R]]
[[Category: Mac Sweeney A]]
[[Category: Maibaum J]]
[[Category: Mainolfi N]]
[[Category: Mogi M]]
[[Category: Sedrani R]]
[[Category: Sellner H]]
[[Category: Sirockin F]]
[[Category: Smith TM]]
[[Category: Valeur E]]
[[Category: Wiesmann C]]