3q4b

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{{STRUCTURE_3q4b| PDB=3q4b | SCENE= }}
 
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===Clinically Useful Alkyl Amine Renin Inhibitors===
 
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==Disease==
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==Clinically Useful 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='3q4b' size='340' side='right'caption='[[3q4b]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3q4b]] 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=3Q4B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3Q4B 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]] 2.19&#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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RX5:METHYL+(2-{(R)-(3-CHLOROPHENYL)[(3R)-1-({(2S)-2-(METHYLAMINO)-3-[(3R)-TETRAHYDRO-2H-PYRAN-3-YL]PROPYL}CARBAMOYL)PIPERIDIN-3-YL]METHOXY}ETHYL)CARBAMATE'>RX5</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=3q4b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3q4b OCA], [https://pdbe.org/3q4b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3q4b RCSB], [https://www.ebi.ac.uk/pdbsum/3q4b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3q4b 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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, &gt;15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
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==Function==
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Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.,Jia L, Simpson RD, Yuan J, Xu Z, Zhao W, Cacatian S, Tice CM, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Bukhtiyarov Y, Johnson JA, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA ACS Med Chem Lett. 2011 Aug 9;2(10):747-51. doi: 10.1021/ml200137x. eCollection, 2011 Oct 13. PMID:24900262<ref>PMID:24900262</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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[[3q4b]] 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=3Q4B OCA].
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</div>
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<div class="pdbe-citations 3q4b" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
*[[Renin|Renin]]
*[[Renin|Renin]]
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== References ==
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==Reference==
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<references/>
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<references group="xtra"/><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: Glycoprotein]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Hypertension]]
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[[Category: Membrane]]
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[[Category: Protease]]
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[[Category: Renin expression]]
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[[Category: Renin inhibitor]]
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[[Category: Secreted]]
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Current revision

Clinically Useful Alkyl Amine Renin Inhibitors

PDB ID 3q4b

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