6o1s: Difference between revisions
New page: '''Unreleased structure''' The entry 6o1s is ON HOLD Authors: Partridge, J.R., Choy, R.M. Description: Structure of human plasma kallikrein protease domain with inhibitor [[Category: U... |
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==Structure of human plasma kallikrein protease domain with inhibitor== | |||
<StructureSection load='6o1s' size='340' side='right'caption='[[6o1s]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6o1s]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5tz9 5tz9]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O1S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O1S 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]] 1.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7SD:N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-({4-[(1H-pyrazol-1-yl)methyl]phenyl}methyl)-1H-pyrazole-4-carboxamide'>7SD</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=6o1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o1s OCA], [https://pdbe.org/6o1s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o1s RCSB], [https://www.ebi.ac.uk/pdbsum/6o1s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o1s ProSAT]</span></td></tr> | |||
</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 == | |||
Plasma kallikrein (pKal) is a serine protease responsible for cleaving high-molecular-weight kininogen to produce the pro-inflammatory peptide, bradykinin. Unregulated pKal activity can lead to hereditary angioedema (HAE) following excess bradykinin release. HAE attacks can lead to a compromised airway that can be life threatening. As there are limited agents for prophylaxis of HAE attacks, there is a high unmet need for a therapeutic agent for regulating pKal with a high degree of specificity. Here we present crystal structures of both full-length and the protease domain of pKal, bound to two very distinct classes of small-molecule inhibitors: compound 1, and BCX4161. Both inhibitors demonstrate low nM inhibitory potency for pKal and varying specificity for related serine proteases. Compound 1 utilizes a surprising mode of interaction and upon binding results in a rearrangement of the binding pocket. Co-crystal structures of pKal describes why this class of small-molecule inhibitor is potent. Lack of conservation in surrounding residues explains the approximately 10,000-fold specificity over structurally similar proteases, as shown by in vitro protease inhibition data. Structural information, combined with biochemical and enzymatic analyses, provides a novel scaffold for the design of targeted oral small molecule inhibitors of pKal for treatment of HAE and other diseases resulting from unregulated plasma kallikrein activity. | |||
Structures of full-length plasma kallikrein bound to highly specific inhibitors describe a new mode of targeted inhibition.,Partridge JR, Choy RM, Silva-Garcia A, Yu C, Li Z, Sham H, Metcalf B J Struct Biol. 2019 Mar 12. pii: S1047-8477(19)30046-2. doi:, 10.1016/j.jsb.2019.03.001. PMID:30876891<ref>PMID:30876891</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Choy | <div class="pdbe-citations 6o1s" style="background-color:#fffaf0;"></div> | ||
[[Category: Partridge | |||
==See Also== | |||
*[[Kallikrein 3D structures|Kallikrein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Choy RM]] | |||
[[Category: Partridge JR]] | |||
Latest revision as of 10:03, 11 October 2023
Structure of human plasma kallikrein protease domain with inhibitorStructure of human plasma kallikrein protease domain with inhibitor
Structural highlights
DiseaseKLKB1_HUMAN Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:612423; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect. FunctionKLKB1_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. Publication Abstract from PubMedPlasma kallikrein (pKal) is a serine protease responsible for cleaving high-molecular-weight kininogen to produce the pro-inflammatory peptide, bradykinin. Unregulated pKal activity can lead to hereditary angioedema (HAE) following excess bradykinin release. HAE attacks can lead to a compromised airway that can be life threatening. As there are limited agents for prophylaxis of HAE attacks, there is a high unmet need for a therapeutic agent for regulating pKal with a high degree of specificity. Here we present crystal structures of both full-length and the protease domain of pKal, bound to two very distinct classes of small-molecule inhibitors: compound 1, and BCX4161. Both inhibitors demonstrate low nM inhibitory potency for pKal and varying specificity for related serine proteases. Compound 1 utilizes a surprising mode of interaction and upon binding results in a rearrangement of the binding pocket. Co-crystal structures of pKal describes why this class of small-molecule inhibitor is potent. Lack of conservation in surrounding residues explains the approximately 10,000-fold specificity over structurally similar proteases, as shown by in vitro protease inhibition data. Structural information, combined with biochemical and enzymatic analyses, provides a novel scaffold for the design of targeted oral small molecule inhibitors of pKal for treatment of HAE and other diseases resulting from unregulated plasma kallikrein activity. Structures of full-length plasma kallikrein bound to highly specific inhibitors describe a new mode of targeted inhibition.,Partridge JR, Choy RM, Silva-Garcia A, Yu C, Li Z, Sham H, Metcalf B J Struct Biol. 2019 Mar 12. pii: S1047-8477(19)30046-2. doi:, 10.1016/j.jsb.2019.03.001. PMID:30876891[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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