1h1b - Revision history

OCA at 12:13, 13 December 2023

OCA — Wed, 13 Dec 2023 12:13:59 GMT

←Older revision		Revision as of 12:13, 13 December 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[1h1b]] is a 2 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=1H1B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H1B FirstGlance]. <br>		<table><tr><td colspan='2'>[[1h1b]] is a 2 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=1H1B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H1B FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=151:(2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC+ACID'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 2Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=151:(2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC+ACID'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span></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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [https://pdbe.org/1h1b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [https://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h1b ProSAT]</span></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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [https://pdbe.org/1h1b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [https://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h1b ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[https://omim.org/entry/162800 162800]]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[https://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>	+	[https://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[https://omim.org/entry/162800 162800]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[https://omim.org/entry/202700 202700]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.<ref>PMID:15140022</ref>	+	[https://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.<ref>PMID:15140022</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 41:		Line 40:
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Leukocyte elastase]]~~	+	[[Category: Amour A]]
-	[[Category: Amour, A]]	+	[[Category: Clarke GDE]]
-	[[Category: Clarke~~, G D.E~~]]	+	[[Category: Dixon M]]
-	[[Category: Dixon, M]]	+	[[Category: Dowle MD]]
-	[[Category: Dowle~~, M D~~]]	+	[[Category: Fleetwood G]]
-	[[Category: Fleetwood, G]]	+	[[Category: Godward RE]]
-	[[Category: Godward~~, R E~~]]	+	[[Category: Hardy GW]]
-	[[Category: Hardy~~, G W~~]]	+	[[Category: Harrison LA]]
-	[[Category: Harrison~~, L A~~]]	+	[[Category: Hodgson ST]]
-	[[Category: Hodgson~~, S T~~]]	+	[[Category: Humphreys DC]]
-	[[Category: Humphreys~~, D C~~]]	+	[[Category: Inglis GGA]]
-	[[Category: Inglis~~, G G.A~~]]	+	[[Category: Johnson MR]]
-	[[Category: Johnson~~, M R~~]]	+	[[Category: Macdonald SJF]]
-	[[Category: Macdonald~~, S J.F~~]]	+	[[Category: Molloy CR]]
-	[[Category: Molloy~~, C R~~]]	+	[[Category: Singh OMP]]
-	[[Category: Singh~~, O M.P~~]]	+	[[Category: Smith RA]]
-	[[Category: Smith~~, R A~~]]	+	[[Category: Wonacott AJ]]
-	[[Category: Wonacott~~, A J]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Serine protease~~]]	+

OCA at 09:15, 24 February 2021

OCA — Wed, 24 Feb 2021 09:15:53 GMT

←Older revision		Revision as of 09:15, 24 February 2021
Line 1:		Line 1:

-	====	+	==Crystal structure of human neutrophil elastase complexed with an inhibitor (GW475151)==
-	<StructureSection load='1h1b' size='340' side='right'caption='[[1h1b]]' scene=''>	+	<StructureSection load='1h1b' size='340' side='right'caption='[[1h1b]], [[Resolution\|resolution]] 2.00Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[1h1b]] is a 2 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=1H1B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H1B 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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [https://pdbe.org/1h1b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [https://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h1b 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=151:(2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC+ACID'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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;'>[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</div></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span></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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [https://pdbe.org/1h1b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [https://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h1b ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[https://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[https://omim.org/entry/162800 162800]]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[https://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.<ref>PMID:15140022</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 16:		Line 23:
	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1h1b ConSurf].		</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1h1b ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.
		+
		+	Discovery of further pyrrolidine trans-lactams as inhibitors of human neutrophil elastase (HNE) with potential as development candidates and the crystal structure of HNE complexed with an inhibitor (GW475151).,Macdonald SJ, Dowle MD, Harrison LA, Clarke GD, Inglis GG, Johnson MR, Shah P, Smith RA, Amour A, Fleetwood G, Humphreys DC, Molloy CR, Dixon M, Godward RE, Wonacott AJ, Singh OM, Hodgson ST, Hardy GW J Med Chem. 2002 Aug 29;45(18):3878-90. PMID:12190311<ref>PMID:12190311</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 1h1b" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Elastase 3D structures\|Elastase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Leukocyte elastase]]
		+	[[Category: Amour, A]]
		+	[[Category: Clarke, G D.E]]
		+	[[Category: Dixon, M]]
		+	[[Category: Dowle, M D]]
		+	[[Category: Fleetwood, G]]
		+	[[Category: Godward, R E]]
		+	[[Category: Hardy, G W]]
		+	[[Category: Harrison, L A]]
		+	[[Category: Hodgson, S T]]
		+	[[Category: Humphreys, D C]]
		+	[[Category: Inglis, G G.A]]
		+	[[Category: Johnson, M R]]
		+	[[Category: Macdonald, S J.F]]
		+	[[Category: Molloy, C R]]
		+	[[Category: Singh, O M.P]]
		+	[[Category: Smith, R A]]
		+	[[Category: Wonacott, A J]]
		+	[[Category: Hydrolase]]
		+	[[Category: Serine protease]]

OCA at 07:05, 24 February 2021

OCA — Wed, 24 Feb 2021 07:05:30 GMT

←Older revision		Revision as of 07:05, 24 February 2021
Line 1:		Line 1:

-	==~~Crystal structure of human neutrophil elastase complexed with an inhibitor (GW475151)~~==	+	====
-	<StructureSection load='1h1b' size='340' side='right'caption='[[1h1b]]~~, [[Resolution\|resolution]] 2.00Å~~' scene=''>	+	<StructureSection load='1h1b' size='340' side='right'caption='[[1h1b]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[1h1b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens].~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=~~1H1B~~ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=~~1H1B~~ FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=151:(2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC+ACID'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>	+	</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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [https://pdbe.org/1h1b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [https://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h1b ProSAT]</span></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</td></tr>~~	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [~~http~~://pdbe.org/1h1b PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=1h1b ProSAT]</span></td></tr>	+
	</table>		</table>
-	== Disease ==
-	[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[http://omim.org/entry/162800 162800]]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[http://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>
-	== Function ==
-	[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.<ref>PMID:15140022</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 23:		Line 16:
	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1h1b ConSurf].		</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1h1b ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.
-
-	Discovery of further pyrrolidine trans-lactams as inhibitors of human neutrophil elastase (HNE) with potential as development candidates and the crystal structure of HNE complexed with an inhibitor (GW475151).,Macdonald SJ, Dowle MD, Harrison LA, Clarke GD, Inglis GG, Johnson MR, Shah P, Smith RA, Amour A, Fleetwood G, Humphreys DC, Molloy CR, Dixon M, Godward RE, Wonacott AJ, Singh OM, Hodgson ST, Hardy GW J Med Chem. 2002 Aug 29;45(18):3878-90. PMID:12190311<ref>PMID:12190311</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 1h1b" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Elastase\|Elastase]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Leukocyte elastase]]~~	+	[[Category: Z-disk]]
-	~~[[Category: Amour, A]]~~	+
-	~~[[Category: Clarke, G D.E]]~~	+
-	~~[[Category: Dixon, M]]~~	+
-	~~[[Category: Dowle, M D]]~~	+
-	~~[[Category: Fleetwood, G]]~~	+
-	~~[[Category: Godward, R E]]~~	+
-	~~[[Category: Hardy, G W]]~~	+
-	~~[[Category: Harrison, L A]]~~	+
-	~~[[Category: Hodgson, S T]]~~	+
-	~~[[Category: Humphreys, D C]]~~	+
-	~~[[Category: Inglis, G G.A]]~~	+
-	~~[[Category: Johnson, M R]]~~	+
-	~~[[Category: Macdonald, S J.F]]~~	+
-	~~[[Category: Molloy, C R]]~~	+
-	~~[[Category: Singh, O M.P]]~~	+
-	~~[[Category: Smith, R A]]~~	+
-	~~[[Category: Wonacott, A J]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Serine protease~~]]	+

OCA at 11:36, 10 May 2019

OCA — Fri, 10 May 2019 11:36:08 GMT

←Older revision		Revision as of 11:36, 10 May 2019
Line 1:		Line 1:

	==Crystal structure of human neutrophil elastase complexed with an inhibitor (GW475151)==		==Crystal structure of human neutrophil elastase complexed with an inhibitor (GW475151)==
-	<StructureSection load='1h1b' size='340' side='right' caption='[[1h1b]], [[Resolution\|resolution]] 2.00Å' scene=''>	+	<StructureSection load='1h1b' size='340' side='right'caption='[[1h1b]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[1h1b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H1B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1H1B FirstGlance]. <br>		<table><tr><td colspan='2'>[[1h1b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H1B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1H1B FirstGlance]. <br>
Line 32:		Line 32:
	</div>		</div>
	<div class="pdbe-citations 1h1b" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 1h1b" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Elastase\|Elastase]]
	== References ==		== References ==
	<references/>		<references/>
Line 37:		Line 40:
	</StructureSection>		</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
	[[Category: Leukocyte elastase]]		[[Category: Leukocyte elastase]]
	[[Category: Amour, A]]		[[Category: Amour, A]]

OCA at 06:27, 3 January 2018

OCA — Wed, 03 Jan 2018 06:27:18 GMT

←Older revision		Revision as of 06:27, 3 January 2018
Line 1:		Line 1:
-	==~~CRYSTAL STRUCTURE OF HUMAN NEUTROPHIL ELASTASE COMPLEXED WITH AN INHIBITOR~~ (GW475151)==	+
		+	==Crystal structure of human neutrophil elastase complexed with an inhibitor (GW475151)==
	<StructureSection load='1h1b' size='340' side='right' caption='[[1h1b]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='1h1b' size='340' side='right' caption='[[1h1b]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://pdbe.org/1h1b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum]</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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://pdbe.org/1h1b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1h1b ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 16:		Line 17:
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h1/1h1b_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h1/1h1b_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
Line 31:		Line 32:
	</div>		</div>
	<div class="pdbe-citations 1h1b" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 1h1b" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Elastase\|Elastase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 02:57, 10 February 2016

OCA — Wed, 10 Feb 2016 02:57:10 GMT

←Older revision		Revision as of 02:57, 10 February 2016
Line 20:		Line 20:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1h1b ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">

OCA at 04:41, 11 September 2015

OCA — Fri, 11 Sep 2015 04:41:55 GMT

←Older revision		Revision as of 04:41, 11 September 2015
Line 6:		Line 6:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum]</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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://pdbe.org/1h1b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 30:		Line 30:
	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 1h1b" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 18:31, 22 December 2014

OCA — Mon, 22 Dec 2014 18:31:08 GMT

←Older revision		Revision as of 18:31, 22 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[1h1b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H1B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1H1B FirstGlance]. <br>		<table><tr><td colspan='2'>[[1h1b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H1B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1H1B FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=151:(2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC+ACID'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=151:(2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC+ACID'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</td></tr>
-	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span></td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum]</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=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum]</span></td></tr>
-	<table>	+	</table>
	== Disease ==		== Disease ==
	[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[http://omim.org/entry/162800 162800]]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[http://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>		[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[http://omim.org/entry/162800 162800]]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[http://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>
Line 39:		Line 39:
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Leukocyte elastase]]		[[Category: Leukocyte elastase]]
-	[[Category: Amour, A.]]	+	[[Category: Amour, A]]
-	[[Category: Clarke, G D.E.]]	+	[[Category: Clarke, G D.E]]
-	[[Category: Dixon, M.]]	+	[[Category: Dixon, M]]
-	[[Category: Dowle, M D.]]	+	[[Category: Dowle, M D]]
-	[[Category: Fleetwood, G.]]	+	[[Category: Fleetwood, G]]
-	[[Category: Godward, R E.]]	+	[[Category: Godward, R E]]
-	[[Category: Hardy, G W.]]	+	[[Category: Hardy, G W]]
-	[[Category: Harrison, L A.]]	+	[[Category: Harrison, L A]]
-	[[Category: Hodgson, S T.]]	+	[[Category: Hodgson, S T]]
-	[[Category: Humphreys, D C.]]	+	[[Category: Humphreys, D C]]
-	[[Category: Inglis, G G.A.]]	+	[[Category: Inglis, G G.A]]
-	[[Category: Johnson, M R.]]	+	[[Category: Johnson, M R]]
-	[[Category: Macdonald, S J.F.]]	+	[[Category: Macdonald, S J.F]]
-	[[Category: Molloy, C R.]]	+	[[Category: Molloy, C R]]
-	[[Category: Singh, O M.P.]]	+	[[Category: Singh, O M.P]]
-	[[Category: Smith, R A.]]	+	[[Category: Smith, R A]]
-	[[Category: Wonacott, A J.]]	+	[[Category: Wonacott, A J]]
	[[Category: Hydrolase]]		[[Category: Hydrolase]]
	[[Category: Serine protease]]		[[Category: Serine protease]]

OCA at 14:01, 29 September 2014

OCA — Mon, 29 Sep 2014 14:01:06 GMT

←Older revision		Revision as of 14:01, 29 September 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_1h1b\| PDB=1h1b \| SCENE= }}~~	+	==CRYSTAL STRUCTURE OF HUMAN NEUTROPHIL ELASTASE COMPLEXED WITH AN INHIBITOR (GW475151)==
-	===CRYSTAL STRUCTURE OF HUMAN NEUTROPHIL ELASTASE COMPLEXED WITH AN INHIBITOR (GW475151)===	+	<StructureSection load='1h1b' size='340' side='right' caption='[[1h1b]], [[Resolution\|resolution]] 2.00Å' scene=''>
-	{~~{ABSTRACT_PUBMED_12190311}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[1h1b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H1B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1H1B FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=151:(2S)-3-METHYL-2-((2R,3S)-3-[(METHYLSULFONYL)AMINO]-1-{[2-(PYRROLIDIN-1-YLMETHYL)-1,3-OXAZOL-4-YL]CARBONYL}PYRROLIDIN-2-YL)BUTANOIC+ACID'>151</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1b0f\|1b0f]], [[1hne\|1hne]], [[1ppf\|1ppf]], [[1ppg\|1ppg]]</td></tr>
		+	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukocyte_elastase Leukocyte elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.37 3.4.21.37] </span></td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h1b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1h1b RCSB], [http://www.ebi.ac.uk/pdbsum/1h1b PDBsum]</span></td></tr>
		+	<table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[http://omim.org/entry/162800 162800]]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref> <ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[http://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.<ref>PMID:15140022</ref>
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h1/1h1b_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.

-	~~==Disease==~~	+	Discovery of further pyrrolidine trans-lactams as inhibitors of human neutrophil elastase (HNE) with potential as development candidates and the crystal structure of HNE complexed with an inhibitor (GW475151).,Macdonald SJ, Dowle MD, Harrison LA, Clarke GD, Inglis GG, Johnson MR, Shah P, Smith RA, Amour A, Fleetwood G, Humphreys DC, Molloy CR, Dixon M, Godward RE, Wonacott AJ, Singh OM, Hodgson ST, Hardy GW J Med Chem. 2002 Aug 29;45(18):3878-90. PMID:12190311<ref>PMID:12190311</ref>
-	~~[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause~~ of ~~cyclic haematopoiesis~~ (CH) ~~[MIM:[http://omim.org/entry/162800 162800]]; also known~~ as ~~cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from~~ the ~~bone marrow oscillates~~ with ~~21-day periodicity~~. ~~Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia~~, ~~affected individuals are at risk for opportunistic infection. Monocytes~~, ~~platelets~~, ~~lymphocytes and reticulocytes also cycle with the same frequency~~.~~<ref>PMID:14673143</ref><ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1~~ (~~SCN1~~) ~~[MIM~~:~~[http~~://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:~~20220065~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http:~~/~~/www~~.~~uniprot~~.~~org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Modifies the functions~~ of ~~natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis~~.<~~ref~~>~~PMID:15140022~~</~~ref~~>	+	</div>
-		+
-	~~==About this Structure==~~	+
-	[[1h1b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H1B OCA].	+

	==See Also==		==See Also==
	*[[Elastase\|Elastase]]		*[[Elastase\|Elastase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:012190311</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Leukocyte elastase]]		[[Category: Leukocyte elastase]]

OCA at 23:04, 24 March 2013

OCA — Sun, 24 Mar 2013 23:04:08 GMT

←Older revision		Revision as of 23:04, 24 March 2013
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-	[[Image:1h1b.png\|left\|200px]]
-
	{{STRUCTURE_1h1b\| PDB=1h1b \| SCENE= }}		{{STRUCTURE_1h1b\| PDB=1h1b \| SCENE= }}
-
	===CRYSTAL STRUCTURE OF HUMAN NEUTROPHIL ELASTASE COMPLEXED WITH AN INHIBITOR (GW475151)===		===CRYSTAL STRUCTURE OF HUMAN NEUTROPHIL ELASTASE COMPLEXED WITH AN INHIBITOR (GW475151)===
		+	{{ABSTRACT_PUBMED_12190311}}

-	~~{{ABSTRACT_PUBMED_12190311}}~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:[http://omim.org/entry/162800 162800]]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.<ref>PMID:14673143</ref><ref>PMID:10581030</ref> Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:[http://omim.org/entry/202700 202700]]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.<ref>PMID:20220065</ref>
		+
		+	==Function==
		+	[[http://www.uniprot.org/uniprot/ELNE_HUMAN ELNE_HUMAN]] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.<ref>PMID:15140022</ref>

	==About this Structure==		==About this Structure==
Line 14:		Line 16:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:012190311</ref><references group="xtra"/>	+	<ref group="xtra">PMID:012190311</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Leukocyte elastase]]		[[Category: Leukocyte elastase]]