2fs4: Difference between revisions

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OCA

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-[[Image:2fs4.gif|left|200px]]<br />
-<applet load="2fs4" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="2fs4, resolution 2.2&Aring;" />
-'''Ketopiperazine-Based Renin Inhibitors: Optimization of the C ring'''<br />
-==Overview==
+==Ketopiperazine-Based Renin Inhibitors: Optimization of the C ring==
-A systematic investigation of the S3 sub-pocket activity requirements was, conducted. It was observed that linear and sterically small side chain, substituents are preferred in the S3 sub-pocket for optimal renin, inhibition. Polar groups in the S3-sub-pocket were not well tolerated and, caused a reduction in renin inhibitory activity. Further, compounds with, clog P's &lt; or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory, activity.
+<StructureSection load='2fs4' size='340' side='right'caption='[[2fs4]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2fs4]] 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=2FS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FS4 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]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PZ1:(6R)-6-({[1-(3-HYDROXYPROPYL)-1,7-DIHYDROQUINOLIN-7-YL]OXY}METHYL)-1-(4-{3-[(2-METHOXYBENZYL)OXY]PROPOXY}PHENYL)PIPERAZIN-2-ONE'>PZ1</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=2fs4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fs4 OCA], [https://pdbe.org/2fs4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fs4 RCSB], [https://www.ebi.ac.uk/pdbsum/2fs4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fs4 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[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 ==
+[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.
+== 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/fs/2fs4_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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/main_output.php?pdb_ID=2fs4 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's &lt; or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
-==Disease==
+Ketopiperazine-based renin inhibitors: optimization of the "C" ring.,Holsworth DD, Cai C, Cheng XM, Cody WL, Downing DM, Erasga N, Lee C, Powell NA, Edmunds JJ, Stier M, Jalaie M, Zhang E, McConnell P, Ryan MJ, Bryant J, Li T, Kasani A, Hall E, Subedi R, Rahim M, Maiti S Bioorg Med Chem Lett. 2006 May 1;16(9):2500-4. Epub 2006 Feb 15. PMID:16480874<ref>PMID:16480874</ref>
-Known diseases associated with this structure: Hyperproreninemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=179820 179820]], Renal tubular dysgenesis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=179820 179820]]
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-FS4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with PZ1 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2FS4 OCA].
+</div>
+<div class="pdbe-citations 2fs4" style="background-color:#fffaf0;"></div>
-==Reference==
+==See Also==
-Ketopiperazine-based renin inhibitors: optimization of the "C" ring., Holsworth DD, Cai C, Cheng XM, Cody WL, Downing DM, Erasga N, Lee C, Powell NA, Edmunds JJ, Stier M, Jalaie M, Zhang E, McConnell P, Ryan MJ, Bryant J, Li T, Kasani A, Hall E, Subedi R, Rahim M, Maiti S, Bioorg Med Chem Lett. 2006 May 1;16(9):2500-4. Epub 2006 Feb 15. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16480874 16480874]
+*[[Renin|Renin]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Renin]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Bryant J]]
-[[Category: Bryantb, J.]]
+[[Category: Cai C]]
-[[Category: C.]]
+[[Category: Cheng X-M]]
-[[Category: Caia, C.]]
+[[Category: Cody WL]]
-[[Category: Chenga, X.M.]]
+[[Category: Downing DM]]
-[[Category: Codya, W.L.]]
+[[Category: Edmunds JJ]]
-[[Category: Downinga, D.M.]]
+[[Category: Erasga N]]
-[[Category: Edmundsa, J.J.]]
+[[Category: Hall E]]
-[[Category: Erasgaa, N.]]
+[[Category: Holsworth DD]]
-[[Category: Hallc, E.]]
+[[Category: Jalaie M]]
-[[Category: Holsworth, D.D.]]
+[[Category: Kasani A]]
-[[Category: Jalaiea, M.]]
+[[Category: Lee C]]
-[[Category: Kasanic, A.]]
+[[Category: Li T]]
-[[Category: Leea,]]
+[[Category: Maiti S]]
-[[Category: Lic, T.]]
+[[Category: McConnell P]]
-[[Category: Maitic, S.]]
+[[Category: Powell NA]]
-[[Category: McConnella, P.]]
+[[Category: Rahim M]]
-[[Category: Powella, N.A.]]
+[[Category: Ryan MJ]]
-[[Category: Rahimc, M.]]
+[[Category: Stier M]]
-[[Category: Ryanb, M.J.]]
+[[Category: Subedi R]]
-[[Category: Stiera, M.]]
+[[Category: Zhang E]]
-[[Category: Subedic, R.]]
-[[Category: Zhanga, E.]]
-[[Category: PZ1]]
-[[Category: protein-ligand complexes]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:09:44 2007''