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[[Image:2fs4.gif|left|200px]]


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==Ketopiperazine-Based Renin Inhibitors: Optimization of the C ring==
The line below this paragraph, containing "STRUCTURE_2fs4", creates the "Structure Box" on the page.
<StructureSection load='2fs4' size='340' side='right'caption='[[2fs4]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2fs4]] 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=2FS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FS4 FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
-->
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PZ1:(6R)-6-({[1-(3-HYDROXYPROPYL)-1,7-DIHYDROQUINOLIN-7-YL]OXY}METHYL)-1-(4-{3-[(2-METHOXYBENZYL)OXY]PROPOXY}PHENYL)PIPERAZIN-2-ONE'>PZ1</scene></td></tr>
{{STRUCTURE_2fs4| PDB=2fs4  | SCENE= }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2fs4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fs4 OCA], [https://pdbe.org/2fs4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fs4 RCSB], [https://www.ebi.ac.uk/pdbsum/2fs4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fs4 ProSAT]</span></td></tr>
 
</table>
'''Ketopiperazine-Based Renin Inhibitors: Optimization of the C ring'''
== 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 ==
==Overview==
[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.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fs/2fs4_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2fs4 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's &lt; or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's &lt; or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.


==Disease==
Ketopiperazine-based renin inhibitors: optimization of the "C" ring.,Holsworth DD, Cai C, Cheng XM, Cody WL, Downing DM, Erasga N, Lee C, Powell NA, Edmunds JJ, Stier M, Jalaie M, Zhang E, McConnell P, Ryan MJ, Bryant J, Li T, Kasani A, Hall E, Subedi R, Rahim M, Maiti S Bioorg Med Chem Lett. 2006 May 1;16(9):2500-4. Epub 2006 Feb 15. PMID:16480874<ref>PMID:16480874</ref>
Known disease associated with this structure: Renal tubular dysgenesis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=179820 179820]], Hyperproreninemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=179820 179820]]


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2FS4 is a [[Single protein]] structure of 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=2FS4 OCA].
</div>
<div class="pdbe-citations 2fs4" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Ketopiperazine-based renin inhibitors: optimization of the "C" ring., Holsworth DD, Cai C, Cheng XM, Cody WL, Downing DM, Erasga N, Lee C, Powell NA, Edmunds JJ, Stier M, Jalaie M, Zhang E, McConnell P, Ryan MJ, Bryant J, Li T, Kasani A, Hall E, Subedi R, Rahim M, Maiti S, Bioorg Med Chem Lett. 2006 May 1;16(9):2500-4. Epub 2006 Feb 15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16480874 16480874]
*[[Renin|Renin]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Renin]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Bryant J]]
[[Category: Bryantb, J.]]
[[Category: Cai C]]
[[Category: C.]]
[[Category: Cheng X-M]]
[[Category: Caia, C.]]
[[Category: Cody WL]]
[[Category: Chenga, X M.]]
[[Category: Downing DM]]
[[Category: Codya, W L.]]
[[Category: Edmunds JJ]]
[[Category: Downinga, D M.]]
[[Category: Erasga N]]
[[Category: Edmundsa, J J.]]
[[Category: Hall E]]
[[Category: Erasgaa, N.]]
[[Category: Holsworth DD]]
[[Category: Hallc, E.]]
[[Category: Jalaie M]]
[[Category: Holsworth, D D.]]
[[Category: Kasani A]]
[[Category: Jalaiea, M.]]
[[Category: Lee C]]
[[Category: Kasanic, A.]]
[[Category: Li T]]
[[Category: Leea]]
[[Category: Maiti S]]
[[Category: Lic, T.]]
[[Category: McConnell P]]
[[Category: Maitic, S.]]
[[Category: Powell NA]]
[[Category: McConnella, P.]]
[[Category: Rahim M]]
[[Category: Powella, N A.]]
[[Category: Ryan MJ]]
[[Category: Rahimc, M.]]
[[Category: Stier M]]
[[Category: Ryanb, M J.]]
[[Category: Subedi R]]
[[Category: Stiera, M.]]
[[Category: Zhang E]]
[[Category: Subedic, R.]]
[[Category: Zhanga, E.]]
[[Category: Protein-ligand complex]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 04:14:49 2008''

Latest revision as of 11:00, 30 October 2024

Ketopiperazine-Based Renin Inhibitors: Optimization of the C ringKetopiperazine-Based Renin Inhibitors: Optimization of the C ring

Structural highlights

2fs4 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 2.2Å
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.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.

Ketopiperazine-based renin inhibitors: optimization of the "C" ring.,Holsworth DD, Cai C, Cheng XM, Cody WL, Downing DM, Erasga N, Lee C, Powell NA, Edmunds JJ, Stier M, Jalaie M, Zhang E, McConnell P, Ryan MJ, Bryant J, Li T, Kasani A, Hall E, Subedi R, Rahim M, Maiti S Bioorg Med Chem Lett. 2006 May 1;16(9):2500-4. Epub 2006 Feb 15. PMID:16480874[3]

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

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Holsworth DD, Cai C, Cheng XM, Cody WL, Downing DM, Erasga N, Lee C, Powell NA, Edmunds JJ, Stier M, Jalaie M, Zhang E, McConnell P, Ryan MJ, Bryant J, Li T, Kasani A, Hall E, Subedi R, Rahim M, Maiti S. Ketopiperazine-based renin inhibitors: optimization of the "C" ring. Bioorg Med Chem Lett. 2006 May 1;16(9):2500-4. Epub 2006 Feb 15. PMID:16480874 doi:http://dx.doi.org/10.1016/j.bmcl.2006.01.084

2fs4, resolution 2.20Å

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