6o1s - Revision history

OCA at 07:03, 11 October 2023

OCA — Wed, 11 Oct 2023 07:03:12 GMT

←Older revision		Revision as of 07:03, 11 October 2023
Line 3:		Line 3:
	<StructureSection load='6o1s' size='340' side='right'caption='[[6o1s]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='6o1s' size='340' side='right'caption='[[6o1s]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6o1s]] is a 1 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=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 [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6O1S FirstGlance]. <br>	+	<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='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><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>~~	+	</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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6o1g\|6o1g]], [[6bfp\|6bfp]]</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='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">KLKB1, KLK3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Plasma_kallikrein Plasma kallikrein], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.34 3.4.21.34] </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=6o1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o1s OCA], [~~http~~://pdbe.org/6o1s PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6o1s RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6o1s PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6o1s ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/KLKB1_HUMAN KLKB1_HUMAN]] Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:[~~http~~://omim.org/entry/612423 612423]]; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect.	+	[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 ==		== Function ==
-	[~~[http~~://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.	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 25:		Line 23:

	==See Also==		==See Also==
-	*[[Kallikrein\|Kallikrein]]	+	*[[Kallikrein 3D structures\|Kallikrein 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Plasma kallikrein]]~~	+	[[Category: Choy RM]]
-	[[Category: Choy~~, R M~~]]	+	[[Category: Partridge JR]]
-	[[Category: Partridge~~, J R]]~~	+
-	~~[[Category: Blood clotting]]~~	+
-	~~[[Category: Protease~~]]	+

OCA at 07:13, 27 March 2019

OCA — Wed, 27 Mar 2019 07:13:04 GMT

←Older revision		Revision as of 07:13, 27 March 2019
Line 1:		Line 1:

	==Structure of human plasma kallikrein protease domain with inhibitor==		==Structure of human plasma kallikrein protease domain with inhibitor==
-	<StructureSection load='6o1s' size='340' side='right' caption='[[6o1s]], [[Resolution\|resolution]] 1.70Å' scene=''>	+	<StructureSection load='6o1s' size='340' side='right'caption='[[6o1s]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6o1s]] is a 1 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O1S FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6o1s]] is a 1 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=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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O1S FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><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>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6o1g\|6o1g]], [[6bfp\|6bfp]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6o1g\|6o1g]], [[6bfp\|6bfp]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">KLKB1, KLK3 ([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/Plasma_kallikrein Plasma kallikrein], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.34 3.4.21.34] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Plasma_kallikrein Plasma kallikrein], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.34 3.4.21.34] </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=6o1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o1s OCA], [http://pdbe.org/6o1s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o1s RCSB], [http://www.ebi.ac.uk/pdbsum/6o1s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o1s ProSAT]</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=6o1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o1s OCA], [http://pdbe.org/6o1s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o1s RCSB], [http://www.ebi.ac.uk/pdbsum/6o1s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o1s ProSAT]</span></td></tr>
Line 15:		Line 16:
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	~~A series of macrocyclic analogues were designed and synthesized based on the cocrystal structure of small molecule plasma~~ kallikrein (pKal) ~~inhibitor~~, 2, with the ~~pKal~~ protease domain~~. This led to the discovery~~ of ~~a potent macrocyclic~~ pKal ~~inhibitor 29~~, ~~with an IC50~~ of 2 nM for ~~one olefinic isomer~~ and 42.~~3 nM~~ for the other ~~olefinic isomer~~.	+	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.

-	~~Structure~~-~~Guided Design~~ of ~~Novel, Potent, and Selective Macrocyclic Plasma Kallikrein Inhibitors~~.~~,Li Z~~, Partridge J, Silva-Garcia A, ~~Rademacher P~~, ~~Betz A, Xu Q~~, Sham H, ~~Hu Y, Shan Y, Liu~~ B~~, Zhang Y, Shi H, Xu Q, Ma X, Zhang L ACS Med Chem Lett~~. ~~2016 Dec 6;8~~(2)~~:185~~-~~190~~. doi: 10.~~1021~~/~~acsmedchemlett~~.~~6b00384~~. ~~, eCollection 2017 Feb 9~~. PMID:~~28197309~~<ref>PMID:~~28197309~~</ref>	+	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>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
	<div class="pdbe-citations 6o1s" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6o1s" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Kallikrein\|Kallikrein]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Plasma kallikrein]]		[[Category: Plasma kallikrein]]
	[[Category: Choy, R M]]		[[Category: Choy, R M]]

OCA at 07:18, 6 March 2019

OCA — Wed, 06 Mar 2019 07:18:54 GMT

←Older revision		Revision as of 07:18, 6 March 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The~~ entry 6o1s is ~~ON HOLD~~	+	==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. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O1S FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6o1g\|6o1g]], [[6bfp\|6bfp]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Plasma_kallikrein Plasma kallikrein], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.34 3.4.21.34] </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=6o1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o1s OCA], [http://pdbe.org/6o1s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o1s RCSB], [http://www.ebi.ac.uk/pdbsum/6o1s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o1s ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/KLKB1_HUMAN KLKB1_HUMAN]] Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:[http://omim.org/entry/612423 612423]]; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect.
		+	== Function ==
		+	[[http://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 ==
		+	A series of macrocyclic analogues were designed and synthesized based on the cocrystal structure of small molecule plasma kallikrein (pKal) inhibitor, 2, with the pKal protease domain. This led to the discovery of a potent macrocyclic pKal inhibitor 29, with an IC50 of 2 nM for one olefinic isomer and 42.3 nM for the other olefinic isomer.

-	~~Authors: Partridge~~, ~~J.R~~., ~~Choy~~, R.M.	+	Structure-Guided Design of Novel, Potent, and Selective Macrocyclic Plasma Kallikrein Inhibitors.,Li Z, Partridge J, Silva-Garcia A, Rademacher P, Betz A, Xu Q, Sham H, Hu Y, Shan Y, Liu B, Zhang Y, Shi H, Xu Q, Ma X, Zhang L ACS Med Chem Lett. 2016 Dec 6;8(2):185-190. doi: 10.1021/acsmedchemlett.6b00384. , eCollection 2017 Feb 9. PMID:28197309<ref>PMID:28197309</ref>

-	~~Description: Structure~~ of ~~human plasma kallikrein protease domain with inhibitor~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: Choy, R.M]]	+	<div class="pdbe-citations 6o1s" style="background-color:#fffaf0;"></div>
-	[[Category: Partridge, J.R]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Plasma kallikrein]]
		+	[[Category: Choy, R M]]
		+	[[Category: Partridge, J R]]
		+	[[Category: Blood clotting]]
		+	[[Category: Protease]]

OCA: Protected "6o1s" [edit=sysop:move=sysop]

OCA — Wed, 27 Feb 2019 13:51:34 GMT

Protected "6o1s" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:51, 27 February 2019

OCA: 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...

OCA — Wed, 27 Feb 2019 13:51:32 GMT

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...

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: Unreleased Structures]]
[[Category: Choy, R.M]]
[[Category: Partridge, J.R]]