3km4

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{{STRUCTURE_3km4| PDB=3km4 | SCENE= }}
 
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===Optimization of Orally Bioavailable Alkyl Amine Renin Inhibitors===
 
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{{ABSTRACT_PUBMED_19959358}}
 
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==Disease==
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==Optimization of Orally Bioavailable Alkyl Amine Renin Inhibitors==
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[[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>
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<StructureSection load='3km4' size='340' side='right'caption='[[3km4]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3km4]] 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=3KM4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KM4 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=22X:(3R)-3-[(1S)-4-(ACETYLAMINO)-1-(3-CHLOROPHENYL)-1-HYDROXYBUTYL]-N-{(1S)-2-CYCLOHEXYL-1-[(METHYLAMINO)METHYL]ETHYL}PIPERIDINE-1-CARBOXAMIDE'>22X</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3km4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3km4 OCA], [https://pdbe.org/3km4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3km4 RCSB], [https://www.ebi.ac.uk/pdbsum/3km4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3km4 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/km/3km4_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=3km4 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in &gt;20h reduction of blood pressure in a double transgenic rat model of hypertension.
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==Function==
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Optimization of orally bioavailable alkyl amine renin inhibitors.,Xu Z, Cacatian S, Yuan J, Simpson RD, Jia L, Zhao W, Tice CM, Flaherty PT, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Scott BB, Bukhtiyarov Y, Berbaum J, Mason J, Panemangalore R, Cappiello MG, Bentley R, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA Bioorg Med Chem Lett. 2010 Jan 15;20(2):694-9. Epub 2009 Dec 1. PMID:19959358<ref>PMID:19959358</ref>
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[[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.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3km4]] 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=3KM4 OCA].
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</div>
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<div class="pdbe-citations 3km4" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:019959358</ref><references group="xtra"/><references/>
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*[[Renin|Renin]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Renin]]
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[[Category: Large Structures]]
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[[Category: McKeever, B M.]]
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[[Category: McKeever BM]]
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[[Category: Wu, Z.]]
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[[Category: Wu Z]]
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[[Category: Aspartate protease]]
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[[Category: Aspartyl protease]]
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[[Category: Cleavage on pair of basic residue]]
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[[Category: Disulfide bond]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Hypertension]]
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[[Category: Protease]]
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[[Category: Renin]]
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[[Category: Renin expression]]
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[[Category: Renin inhibitor]]
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[[Category: Secreted]]
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[[Category: Zymogen]]
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Current revision

Optimization of Orally Bioavailable Alkyl Amine Renin Inhibitors

PDB ID 3km4

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