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4rz1
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==RENIN IN COMPLEXED WITH (3S,4S)-4-({[4-methoxy-3-(3-methoxypropoxy)benzoyl](propan-2-yl)amino}methyl)pyrrolidin-3-yl benzylcarbamate INHIBITOR== | |
| + | <StructureSection load='4rz1' size='340' side='right'caption='[[4rz1]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4rz1]] 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=4RZ1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RZ1 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3ZN:(3S,4S)-4-({[4-METHOXY-3-(3-METHOXYPROPOXY)BENZOYL](PROPAN-2-YL)AMINO}METHYL)PYRROLIDIN-3-YL+BENZYLCARBAMATE'>3ZN</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4rz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rz1 OCA], [https://pdbe.org/4rz1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rz1 RCSB], [https://www.ebi.ac.uk/pdbsum/4rz1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rz1 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. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g., 2). Based on the X-ray structure of the lead compound 2 bound to renin we predicted that optimization of binding interactions to the prime site could offer an opportunity to further expand the scope of this chemotype. Pyrrolidine-based inhibitors were synthesized in which the prime site moieties are linked to the pyrrolidine core through an oxygen atom, resulting in an ether or a carbamate linker subseries. Especially the carbamate derivatives showed a pronounced increase in in vitro potency compared to 2. Here we report the structure-activity relationship of both subclasses and demonstrate blood pressure lowering effects for an advanced prototype in a hypertensive double-transgenic rat model after oral dosing. | ||
| - | + | trans-3,4-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part II: Prime site exploration using an oxygen linker.,Sellner H, Cottens S, Cumin F, Ehrhardt C, Kosaka T, Lorthiois E, Ostermann N, Webb RL, Rigel DF, Wagner T, Maibaum J Bioorg Med Chem Lett. 2015 Feb 23. pii: S0960-894X(15)00147-X. doi:, 10.1016/j.bmcl.2015.02.040. PMID:25754490<ref>PMID:25754490</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Ostermann | + | <div class="pdbe-citations 4rz1" style="background-color:#fffaf0;"></div> |
| + | |||
| + | ==See Also== | ||
| + | *[[Renin|Renin]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Ostermann N]] | ||
Current revision
RENIN IN COMPLEXED WITH (3S,4S)-4-({[4-methoxy-3-(3-methoxypropoxy)benzoyl](propan-2-yl)amino}methyl)pyrrolidin-3-yl benzylcarbamate INHIBITOR
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