2v0z: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-{{STRUCTURE_2v0z|  PDB=2v0z  |  SCENE=  }}
-===CRYSTAL STRUCTURE OF RENIN WITH INHIBITOR 10 (ALISKIREN)===
-{{ABSTRACT_PUBMED_10903938}}
-==Disease==
+==Crystal Structure of Renin with Inhibitor 10 (Aliskiren)==
-[[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>
+<StructureSection load='2v0z' size='340' side='right'caption='[[2v0z]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2v0z]] 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=2V0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2V0Z 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=C41:ALISKIREN'>C41</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=2v0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v0z OCA], [https://pdbe.org/2v0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2v0z RCSB], [https://www.ebi.ac.uk/pdbsum/2v0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2v0z 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/v0/2v0z_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=2v0z ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+BACKGROUND: The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. RESULTS: Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. CONCLUSIONS: Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.
-==Function==
+Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin.,Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grutter MG Chem Biol. 2000 Jul;7(7):493-504. PMID:10903938<ref>PMID:10903938</ref>
-[[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.
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[2v0z]] 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=2V0Z OCA].
+</div>
+<div class="pdbe-citations 2v0z" style="background-color:#fffaf0;"></div>
 ==See Also==
 *[[Renin|Renin]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:010903938</ref><references group="xtra"/><references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Renin]]
+[[Category: Large Structures]]
-[[Category: Cohen, N C.]]
+[[Category: Cohen NC]]
-[[Category: Cumin, F.]]
+[[Category: Cumin F]]
-[[Category: Fuhrer, W.]]
+[[Category: Fuhrer W]]
-[[Category: Goschke, R.]]
+[[Category: Goschke R]]
-[[Category: Grutter, M G.]]
+[[Category: Grutter MG]]
-[[Category: Maibaum, J.]]
+[[Category: Maibaum J]]
-[[Category: Rahuel, J.]]
+[[Category: Rahuel J]]
-[[Category: Rasetti, V.]]
+[[Category: Rasetti V]]
-[[Category: Rueger, H.]]
+[[Category: Rueger H]]
-[[Category: Stutz, S.]]
+[[Category: Stutz S]]
-[[Category: Wood, J M.]]
+[[Category: Wood JM]]
-[[Category: Aspartyl protease]]
-[[Category: Cleavage on pair of basic residue]]
-[[Category: Glycoprotein]]
-[[Category: Hydrolase]]
-[[Category: Inhibitor-complex]]
-[[Category: Protease]]
-[[Category: Zymogen]]