This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
3g70
From Proteopedia
(Difference between revisions)
| (8 intermediate revisions not shown.) | |||
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Design and Preparation of Potent, Non-Peptidic, Bioavailable Renin Inhibitors== | |
| + | <StructureSection load='3g70' size='340' side='right'caption='[[3g70]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[3g70]] 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=3G70 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3G70 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A5T:(1R,5S)-7-{4-[3-(2-CHLORO-3,6-DIFLUOROPHENOXY)PROPYL]PHENYL}-N-CYCLOPROPYL-N-(2,3-DICHLOROBENZYL)-3,9-DIAZABICYCLO[3.3.1]NON-6-ENE-6-CARBOXAMIDE'>A5T</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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">[[3g6z|3g6z]], [[3g72|3g72]]</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://proteopedia.org/fgij/fg.htm?mol=3g70 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g70 OCA], [http://pdbe.org/3g70 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3g70 RCSB], [http://www.ebi.ac.uk/pdbsum/3g70 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3g70 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. | ||
| + | == 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/g7/3g70_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/main_output.php?pdb_ID=3g70 ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo. | ||
| - | + | Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.,Bezencon O, Bur D, Weller T, Richard-Bildstein S, Remen L, Sifferlen T, Corminboeuf O, Grisostomi C, Boss C, Prade L, Delahaye S, Treiber A, Strickner P, Binkert C, Hess P, Steiner B, Fischli W J Med Chem. 2009 Jun 25;52(12):3689-702. PMID:19358611<ref>PMID:19358611</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| + | <div class="pdbe-citations 3g70" style="background-color:#fffaf0;"></div> | ||
| - | + | ==See Also== | |
| + | *[[Renin|Renin]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Human]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Renin]] | ||
| + | [[Category: Bezencon, O]] | ||
| + | [[Category: Boss, C]] | ||
| + | [[Category: Bur, D]] | ||
| + | [[Category: Fischli, W]] | ||
| + | [[Category: Prade, L]] | ||
| + | [[Category: Weller, T]] | ||
| + | [[Category: Aspartyl protease]] | ||
| + | [[Category: Cleavage on pair of basic residue]] | ||
| + | [[Category: Disease mutation]] | ||
| + | [[Category: Glycoprotein]] | ||
| + | [[Category: Human renin]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Membrane]] | ||
| + | [[Category: Protease]] | ||
| + | [[Category: Secreted]] | ||
| + | [[Category: Zymogen]] | ||
Current revision
Design and Preparation of Potent, Non-Peptidic, Bioavailable Renin Inhibitors
| |||||||||||
Categories: Human | Large Structures | Renin | Bezencon, O | Boss, C | Bur, D | Fischli, W | Prade, L | Weller, T | Aspartyl protease | Cleavage on pair of basic residue | Disease mutation | Glycoprotein | Human renin | Hydrolase | Membrane | Protease | Secreted | Zymogen
