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6rav

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Revision as of 08:27, 24 April 2019

Complement factor B protease domain in complex with the reversible inhibitor 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

Structural highlights

6rav is a 2 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 6qsv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	6qsx, 6qsw
Gene:	CFB, BF, BFD (HUMAN)
Activity:	Alternative-complement-pathway C3/C5 convertase, with EC number 3.4.21.47
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CFAB_HUMAN] Defects in CFB are a cause of susceptibility to hemolytic uremic syndrome atypical type 4 (AHUS4) [MIM: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.^[1] ^[2]

Function

[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.

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):240-5. Epub 2006 Dec 20. PMID:17182750 doi:10.1073/pnas.0603420103
↑ Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010 Jun;31(6):E1445-60. doi: 10.1002/humu.21256. PMID:20513133 doi:10.1002/humu.21256
↑ 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. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci U S A. 2019 Mar 29. pii: 1820892116. doi:, 10.1073/pnas.1820892116. PMID:30926668 doi:http://dx.doi.org/10.1073/pnas.1820892116

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6rav"

@@ Line 3: / Line 3: @@
 <StructureSection load='6rav' size='340' side='right'caption='[[6rav]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6rav]] is a 2 chain structure. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=6qsv 6qsv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RAV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RAV FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6rav]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=6qsv 6qsv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RAV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RAV FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JGQ:4-[(2~{S},4~{S})-4-ethoxy-1-[(5-methoxy-7-methyl-1~{H}-indol-4-yl)methyl]piperidin-2-yl]benzoic+acid'>JGQ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6qsx|6qsx]], [[6qsw|6qsw]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CFB, BF, BFD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alternative-complement-pathway_C3/C5_convertase Alternative-complement-pathway C3/C5 convertase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.47 3.4.21.47] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6rav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rav OCA], [http://pdbe.org/6rav PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rav RCSB], [http://www.ebi.ac.uk/pdbsum/6rav PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rav ProSAT]</span></td></tr>
@@ Line 27: / Line 28: @@
 </StructureSection>
 [[Category: Alternative-complement-pathway C3/C5 convertase]]
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Adams, C M]]

6rav

From Proteopedia

Revision as of 08:27, 24 April 2019

Complement factor B protease domain in complex with the reversible inhibitor 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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