4pyv

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of renin in complex with compound4

Structural highlights

4pyv is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.65Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RENI_HUMAN Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM: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).^[1] Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:613092. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.^[2]

Function

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.

Publication Abstract from PubMed

A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.,Ehara T, Irie O, Kosaka T, Kanazawa T, Breitenstein W, Grosche P, Ostermann N, Suzuki M, Kawakami S, Konishi K, Hitomi Y, Toyao A, Gunji H, Cumin F, Schiering N, Wagner T, Rigel DF, Webb RL, Maibaum J, Yokokawa F ACS Med Chem Lett. 2014 Apr 21;5(7):787-92. doi: 10.1021/ml500137b. eCollection, 2014 Jul 10. PMID:25050166^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gribouval O, Gonzales M, Neuhaus T, Aziza J, Bieth E, Laurent N, Bouton JM, Feuillet F, Makni S, Ben Amar H, Laube G, Delezoide AL, Bouvier R, Dijoud F, Ollagnon-Roman E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005 Sep;37(9):964-8. Epub 2005 Aug 14. PMID:16116425 doi:ng1623
↑ Zivna M, Hulkova H, Matignon M, Hodanova K, Vylet'al P, Kalbacova M, Baresova V, Sikora J, Blazkova H, Zivny J, Ivanek R, Stranecky V, Sovova J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gubler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009 Aug;85(2):204-13. Epub 2009 Aug 6. PMID:19664745 doi:10.1016/j.ajhg.2009.07.010
↑ Ehara T, Irie O, Kosaka T, Kanazawa T, Breitenstein W, Grosche P, Ostermann N, Suzuki M, Kawakami S, Konishi K, Hitomi Y, Toyao A, Gunji H, Cumin F, Schiering N, Wagner T, Rigel DF, Webb RL, Maibaum J, Yokokawa F. Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors. ACS Med Chem Lett. 2014 Apr 21;5(7):787-92. doi: 10.1021/ml500137b. eCollection, 2014 Jul 10. PMID:25050166 doi:http://dx.doi.org/10.1021/ml500137b

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4pyv"

Categories: Homo sapiens | Large Structures | Ostermann N | Zink F

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 4pyv is ON HOLD
+==Crystal structure of renin in complex with compound4==
+<StructureSection load='4pyv' size='340' side='right'caption='[[4pyv]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4pyv]] 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=4PYV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PYV 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]] 2.65&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2XF:TERT-BUTYL+{(3S,5R)-5-[CYCLOPROPYL(2,3-DICHLOROBENZYL)CARBAMOYL]PIPERIDIN-3-YL}CARBAMATE'>2XF</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=4pyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pyv OCA], [https://pdbe.org/4pyv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pyv RCSB], [https://www.ebi.ac.uk/pdbsum/4pyv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pyv 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 ==
+A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.
-Authors: Ostermann, Nils, Zink, Florence
+Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.,Ehara T, Irie O, Kosaka T, Kanazawa T, Breitenstein W, Grosche P, Ostermann N, Suzuki M, Kawakami S, Konishi K, Hitomi Y, Toyao A, Gunji H, Cumin F, Schiering N, Wagner T, Rigel DF, Webb RL, Maibaum J, Yokokawa F ACS Med Chem Lett. 2014 Apr 21;5(7):787-92. doi: 10.1021/ml500137b. eCollection, 2014 Jul 10. PMID:25050166<ref>PMID:25050166</ref>
-Description: CRYSTAL STRUCTURE OF RENIN IN COMPLEXED WITH COMPOUND4
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4pyv" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Renin|Renin]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Ostermann N]]
+[[Category: Zink F]]

4pyv

From Proteopedia

Current revision

Crystal structure of renin in complex with compound4

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox