4gj9

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of renin in complex with GP055321 (compound 4)

Structural highlights

4gj9 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 2.6Å
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 small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3sp-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.

A Novel Class of Oral Direct Renin Inhibitors: Highly Potent 3,5-Disubstituted Piperidines bearing a Tricyclic P3-P1 Pharmacophore.,Ostermann N, Ruedisser S, Ehrhardt C, Breitenstein W, Marzinzik AL, Jacoby E, Vangrevelinghe E, Ottl J, Klumpp M, Hartwieg C, Cumin F, Hassiepen U, Trappe J, Sedrani RC, Geisse S, Gerhartz B, Richert P, Francotte E, Wagner T, Kromer M, Kosaka T, Webb RL, Rigel DF, Maibaum JK, Baeschlin DK J Med Chem. 2013 Jan 29. PMID:23360239^[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
↑ Ostermann N, Ruedisser S, Ehrhardt C, Breitenstein W, Marzinzik AL, Jacoby E, Vangrevelinghe E, Ottl J, Klumpp M, Hartwieg C, Cumin F, Hassiepen U, Trappe J, Sedrani RC, Geisse S, Gerhartz B, Richert P, Francotte E, Wagner T, Kromer M, Kosaka T, Webb RL, Rigel DF, Maibaum JK, Baeschlin DK. A Novel Class of Oral Direct Renin Inhibitors: Highly Potent 3,5-Disubstituted Piperidines bearing a Tricyclic P3-P1 Pharmacophore. J Med Chem. 2013 Jan 29. PMID:23360239 doi:http://dx.doi.org/10.1021/jm301706j

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/4gj9"

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

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4gj9]] 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=4GJ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GJ9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0M2:(2R)-1-(3,8-DIHYDRODIBENZO[B,F]PYRROLO[3,4-D]AZEPIN-2(1H)-YL)PROPAN-2-OL'>0M2</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0M2:(2R)-1-(3,8-DIHYDRODIBENZO[B,F]PYRROLO[3,4-D]AZEPIN-2(1H)-YL)PROPAN-2-OL'>0M2</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=4gj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gj9 OCA], [https://pdbe.org/4gj9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gj9 RCSB], [https://www.ebi.ac.uk/pdbsum/4gj9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gj9 ProSAT]</span></td></tr>
 </table>

4gj9

From Proteopedia

Current revision

Crystal structure of renin in complex with GP055321 (compound 4)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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