5t4s - Revision history

OCA at 15:36, 6 March 2024

OCA — Wed, 06 Mar 2024 15:36:32 GMT

←Older revision		Revision as of 15:36, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='5t4s' size='340' side='right'caption='[[5t4s]], [[Resolution\|resolution]] 2.64Å' scene=''>		<StructureSection load='5t4s' size='340' side='right'caption='[[5t4s]], [[Resolution\|resolution]] 2.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5t4s]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T4S OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5T4S FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5t4s]] 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=5T4S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T4S FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=77O:6-CHLORO-N-[(FURAN-2-YL)METHYL]PYRAZIN-2-AMINE'>77O</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PG6:1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE'>PG6</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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]] 2.64Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">REN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=77O:6-CHLORO-N-[(FURAN-2-YL)METHYL]PYRAZIN-2-AMINE'>77O</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PG6:1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE'>PG6</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] </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=5t4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t4s OCA], [https://pdbe.org/5t4s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t4s RCSB], [https://www.ebi.ac.uk/pdbsum/5t4s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t4s ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5t4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t4s OCA], [~~http~~://pdbe.org/5t4s PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5t4s RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5t4s PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5t4s ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:[~~http~~://omim.org/entry/267430 267430]]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).<ref>PMID:16116425</ref> Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:[~~http~~://omim.org/entry/613092 613092]]. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.<ref>PMID:19664745</ref>	+	[https://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:[https://omim.org/entry/267430 267430]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).<ref>PMID:16116425</ref> Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:[https://omim.org/entry/613092 613092]. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.<ref>PMID:19664745</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.	+	[https://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN] Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	A novel approach was conducted for fragment-based lead discovery and applied to renin inhibitors. The biochemical screening of a fragment library against renin provided the hit fragment which showed a characteristic interaction pattern with the target protein. The hit fragment bound only to the S1, S3, and S3SP (S3 subpocket) sites without any interactions with the catalytic aspartate residues (Asp32 and Asp215 (pepsin numbering)). Prior to making chemical modifications to the hit fragment, we first identified its essential binding sites by utilizing the hit fragment's substructures. Second, we created a new and smaller scaffold, which better occupied the identified essential S3 and S3SP sites, by utilizing library synthesis with high-throughput chemistry. We then revisited the S1 site and efficiently explored a good building block attaching to the scaffold with library synthesis. In the library syntheses, the binding modes of each pivotal compound were determined and confirmed by X-ray crystallography and the library was strategically designed by structure-based computational approach not only to obtain a more active compound but also to obtain informative Structure Activity Relationship (SAR). As a result, we obtained a lead compound offering synthetic accessibility as well as the improved in vitro ADMET profiles. The fragments and compounds possessing a characteristic interaction pattern provided new structural insights into renin's active site and the potential to create a new generation of renin inhibitors. In addition, we demonstrated our FBDD strategy integrating highly sensitive biochemical assay, X-ray crystallography, and high-throughput synthesis and in silico library design aimed at fragment morphing at the initial stage was effective to elucidate a pocket profile and a promising lead compound.	+
-		+
-	Novel approach of fragment-based lead discovery applied to renin inhibitors.,Tawada M, Suzuki S, Imaeda Y, Oki H, Snell G, Behnke CA, Kondo M, Tarui N, Tanaka T, Kuroita T, Tomimoto M Bioorg Med Chem. 2016 Nov 15;24(22):6066-6074. doi: 10.1016/j.bmc.2016.09.065., Epub 2016 Sep 28. PMID:27720325<ref>PMID:27720325</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5t4s" style="background-color:#fffaf0;"></div>~~	+

	==See Also==		==See Also==
Line 29:		Line 19:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Renin]]~~	+	[[Category: Behnke CA]]
-	[[Category: Behnke~~, C A~~]]	+	[[Category: Lane W]]
-	[[Category: Lane, W]]	+	[[Category: Okada K]]
-	[[Category: Okada, K]]	+	[[Category: Oki H]]
-	[[Category: Oki, H]]	+	[[Category: Sang BC]]
-	[[Category: Sang~~, B C~~]]	+	[[Category: Snell GP]]
-	[[Category: Snell~~, G P]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Protein-ligand complex~~]]	+

OCA at 11:21, 16 September 2020

OCA — Wed, 16 Sep 2020 11:21:24 GMT

←Older revision		Revision as of 11:21, 16 September 2020
Line 1:		Line 1:

	==Novel Approach of Fragment-Based Lead Discovery applied to Renin Inhibitors==		==Novel Approach of Fragment-Based Lead Discovery applied to Renin Inhibitors==
-	<StructureSection load='5t4s' size='340' side='right' caption='[[5t4s]], [[Resolution\|resolution]] 2.64Å' scene=''>	+	<StructureSection load='5t4s' size='340' side='right'caption='[[5t4s]], [[Resolution\|resolution]] 2.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5t4s]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T4S OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5T4S FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5t4s]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T4S OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5T4S FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=77O:6-CHLORO-N-[(FURAN-2-YL)METHYL]PYRAZIN-2-AMINE'>77O</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PG6:1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE'>PG6</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=77O:6-CHLORO-N-[(FURAN-2-YL)METHYL]PYRAZIN-2-AMINE'>77O</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PG6:1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE'>PG6</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">REN ([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/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] </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=5t4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t4s OCA], [http://pdbe.org/5t4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t4s RCSB], [http://www.ebi.ac.uk/pdbsum/5t4s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t4s ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5t4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t4s OCA], [http://pdbe.org/5t4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t4s RCSB], [http://www.ebi.ac.uk/pdbsum/5t4s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t4s ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 5t4s" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5t4s" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Renin\|Renin]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Renin]]		[[Category: Renin]]
	[[Category: Behnke, C A]]		[[Category: Behnke, C A]]

OCA at 18:30, 26 October 2016

OCA — Wed, 26 Oct 2016 18:30:35 GMT

←Older revision		Revision as of 18:30, 26 October 2016
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5t4s is ~~ON HOLD~~	+	==Novel Approach of Fragment-Based Lead Discovery applied to Renin Inhibitors==
		+	<StructureSection load='5t4s' size='340' side='right' caption='[[5t4s]], [[Resolution\|resolution]] 2.64Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5t4s]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T4S FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=77O:6-CHLORO-N-[(FURAN-2-YL)METHYL]PYRAZIN-2-AMINE'>77O</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PG6:1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE'>PG6</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] </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=5t4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t4s OCA], [http://pdbe.org/5t4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t4s RCSB], [http://www.ebi.ac.uk/pdbsum/5t4s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t4s ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:[http://omim.org/entry/267430 267430]]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).<ref>PMID:16116425</ref> Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:[http://omim.org/entry/613092 613092]]. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.<ref>PMID:19664745</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	A novel approach was conducted for fragment-based lead discovery and applied to renin inhibitors. The biochemical screening of a fragment library against renin provided the hit fragment which showed a characteristic interaction pattern with the target protein. The hit fragment bound only to the S1, S3, and S3SP (S3 subpocket) sites without any interactions with the catalytic aspartate residues (Asp32 and Asp215 (pepsin numbering)). Prior to making chemical modifications to the hit fragment, we first identified its essential binding sites by utilizing the hit fragment's substructures. Second, we created a new and smaller scaffold, which better occupied the identified essential S3 and S3SP sites, by utilizing library synthesis with high-throughput chemistry. We then revisited the S1 site and efficiently explored a good building block attaching to the scaffold with library synthesis. In the library syntheses, the binding modes of each pivotal compound were determined and confirmed by X-ray crystallography and the library was strategically designed by structure-based computational approach not only to obtain a more active compound but also to obtain informative Structure Activity Relationship (SAR). As a result, we obtained a lead compound offering synthetic accessibility as well as the improved in vitro ADMET profiles. The fragments and compounds possessing a characteristic interaction pattern provided new structural insights into renin's active site and the potential to create a new generation of renin inhibitors. In addition, we demonstrated our FBDD strategy integrating highly sensitive biochemical assay, X-ray crystallography, and high-throughput synthesis and in silico library design aimed at fragment morphing at the initial stage was effective to elucidate a pocket profile and a promising lead compound.

-	~~Authors~~:	+	Novel approach of fragment-based lead discovery applied to renin inhibitors.,Tawada M, Suzuki S, Imaeda Y, Oki H, Snell G, Behnke CA, Kondo M, Tarui N, Tanaka T, Kuroita T, Tomimoto M Bioorg Med Chem. 2016 Nov 15;24(22):6066-6074. doi: 10.1016/j.bmc.2016.09.065., Epub 2016 Sep 28. PMID:27720325<ref>PMID:27720325</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5t4s" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Renin]]
		+	[[Category: Behnke, C A]]
		+	[[Category: Lane, W]]
		+	[[Category: Okada, K]]
		+	[[Category: Oki, H]]
		+	[[Category: Sang, B C]]
		+	[[Category: Snell, G P]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Protein-ligand complex]]

OCA: Protected "5t4s" [edit=sysop:move=sysop]

OCA — Fri, 09 Sep 2016 15:42:23 GMT

Protected "5t4s" [edit=sysop:move=sysop]

←Older revision

Revision as of 15:42, 9 September 2016

OCA: New page: '''Unreleased structure''' The entry 5t4s is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Fri, 09 Sep 2016 15:42:22 GMT

New page: '''Unreleased structure''' The entry 5t4s is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 5t4s is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]