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4gj7

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Revision as of 16:21, 11 August 2016

Crystal structure of renin in complex with NVP-BCA079 (compound 12a)

Structural highlights

4gj7 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4gj5, 4gj6
Gene:	REN (HUMAN)
Activity:	Renin, with EC number 3.4.23.15
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

The small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the non-prime and S1' pockets of the rh-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3sp cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration.

The Discovery of Novel Potent trans-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in silico Three-Dimensional (3D) Pharmacophore Searches.,Lorthiois E, Breitenstein W, Cumin F, Ehrhardt C, Francotte E, Jacoby E, Ostermann N, Sellner H, Kosaka T, Webb R, Rigel D, Hassiepen U, Richert P, Wagner T, Maibaum JK J Med Chem. 2013 Feb 20. PMID:23425156^[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
↑ Lorthiois E, Breitenstein W, Cumin F, Ehrhardt C, Francotte E, Jacoby E, Ostermann N, Sellner H, Kosaka T, Webb R, Rigel D, Hassiepen U, Richert P, Wagner T, Maibaum JK. The Discovery of Novel Potent trans-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in silico Three-Dimensional (3D) Pharmacophore Searches. J Med Chem. 2013 Feb 20. PMID:23425156 doi:http://dx.doi.org/10.1021/jm3017078

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/4gj7"

@@ Line 1: / Line 1: @@
 ==Crystal structure of renin in complex with NVP-BCA079 (compound 12a)==
 <StructureSection load='4gj7' size='340' side='right' caption='[[4gj7]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4gj7]] 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=4GJ7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GJ7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4gj7]] 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=4GJ7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GJ7 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0LT:N-{[(3S,4S)-4-BENZYLPYRROLIDIN-3-YL]METHYL}-4-METHOXY-3-(3-METHOXYPROPOXY)-N-(PROPAN-2-YL)BENZAMIDE'>0LT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gj5|4gj5]], [[4gj6|4gj6]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">REN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">REN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gj7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gj7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gj7 RCSB], [http://www.ebi.ac.uk/pdbsum/4gj7 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gj7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gj7 OCA], [http://pdbe.org/4gj7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gj7 RCSB], [http://www.ebi.ac.uk/pdbsum/4gj7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gj7 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4gj7" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 28: / Line 30: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Renin]]
 [[Category: Kroemer, M]]

4gj7

From Proteopedia

Revision as of 16:21, 11 August 2016

Crystal structure of renin in complex with NVP-BCA079 (compound 12a)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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