7n7x: Difference between revisions
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==Crystal structure of BCX7353(ORLADEYO) in complex with human plasma kallikrein serine protease domain at 2.1 angstrom resolution== | ==Crystal structure of BCX7353(ORLADEYO) in complex with human plasma kallikrein serine protease domain at 2.1 angstrom resolution== | ||
<StructureSection load='7n7x' size='340' side='right'caption='[[7n7x]]' scene=''> | <StructureSection load='7n7x' size='340' side='right'caption='[[7n7x]], [[Resolution|resolution]] 2.10Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N7X FirstGlance]. <br> | <table><tr><td colspan='2'>[[7n7x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N7X FirstGlance]. <br> | ||
</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=7n7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n7x OCA], [https://pdbe.org/7n7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n7x RCSB], [https://www.ebi.ac.uk/pdbsum/7n7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n7x ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0RI:Orladeyo'>0RI</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2any|2any]], [[2anw|2anw]], [[5tjx|5tjx]]</div></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=7n7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n7x OCA], [https://pdbe.org/7n7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n7x RCSB], [https://www.ebi.ac.uk/pdbsum/7n7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n7x ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[https://www.uniprot.org/uniprot/KLKB1_HUMAN KLKB1_HUMAN]] Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:[https://omim.org/entry/612423 612423]]; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect. | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/KLKB1_HUMAN KLKB1_HUMAN]] The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration's approval for the prophylactic treatment of HAE attacks in patients 12 years and older. | |||
Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE).,Kotian PL, Wu M, Vadlakonda S, Chintareddy V, Lu P, Juarez L, Kellogg-Yelder D, Chen X, Muppa S, Chambers-Wilson R, Davis Parker C, Williams J, Polach KJ, Zhang W, Raman K, Babu YS J Med Chem. 2021 Sep 9;64(17):12453-12468. doi: 10.1021/acs.jmedchem.1c00511., Epub 2021 Aug 26. PMID:34436898<ref>PMID:34436898</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7n7x" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Kotian P]] | [[Category: Kotian, P]] | ||
[[Category: Krishnan R]] | [[Category: Krishnan, R]] | ||
[[Category: Polach | [[Category: Polach, K J]] | ||
[[Category: Yarlagadda | [[Category: Yarlagadda, B S]] | ||
[[Category: Zhang W]] | [[Category: Zhang, W]] | ||
[[Category: Acute hereditary angioedema]] | |||
[[Category: Blood]] | |||
[[Category: Bradykinin]] | |||
[[Category: Edema]] | |||
[[Category: Fletcher factor]] | |||
[[Category: Hae]] | |||
[[Category: Haw]] | |||
[[Category: Hereditary angioedema]] | |||
[[Category: Hmwk]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Kallikrein]] | |||
[[Category: Kininogenin]] | |||
[[Category: Orladeyo]] | |||
[[Category: Plasma]] | |||
[[Category: Plasma kallikrein-mediated edema]] | |||
[[Category: Serine protease]] | |||