3g72: Difference between revisions

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~~{{Seed}}~~

~~[[Image:3g72.jpg|left|200px]]~~

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==Design and Preparation of Potent, Non-Peptidic, Bioavailable Renin Inhibitors==

~~The line below this paragraph~~, ~~containing~~ "~~STRUCTURE_3g72~~"~~, creates the~~ "~~Structure Box~~" ~~on the page~~.

~~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'>[[3g72]] 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=3G72 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G72 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]] 1.9Å</td></tr>

-->

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A6T:(1S,5R)-7-{4-[3-(2-CHLORO-3,6-DIFLUOROPHENOXY)PROPYL]PHENYL}-N-CYCLOPROPYL-N-(2,3-DICHLOROBENZYL)-3,9-DIAZABICYCLO[3.3.1]NON-6-ENE-6-CARBOXAMIDE'>A6T</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>

~~{{STRUCTURE_3g72| PDB~~=~~3g72 | SCENE~~= }}

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3g72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g72 OCA], [https://pdbe.org/3g72 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g72 RCSB], [https://www.ebi.ac.uk/pdbsum/3g72 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g72 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.

== Evolutionary Conservation ==

[[Image:Consurf_key_small.gif|200px|right]]

Check<jmol>

<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g7/3g72_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=3g72 ConSurf].

== Publication Abstract from PubMed ==

Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.

~~===~~Design and ~~Preparation~~ of ~~Potent~~, ~~Non~~-~~Peptidic~~, ~~Bioavailable Renin Inhibitors===~~

Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.,Bezencon O, Bur D, Weller T, Richard-Bildstein S, Remen L, Sifferlen T, Corminboeuf O, Grisostomi C, Boss C, Prade L, Delahaye S, Treiber A, Strickner P, Binkert C, Hess P, Steiner B, Fischli W J Med Chem. 2009 Jun 25;52(12):3689-702. PMID:19358611<ref>PMID:19358611</ref>

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

</div>

~~<!--~~

==See Also==

~~The line below this paragraph, {{ABSTRACT_PUBMED_19358611}}, adds the Publication Abstract to the page~~

*[[Renin|Renin]]

~~(as it appears on PubMed at http://www.pubmed.gov), where 19358611 is the PubMed ID number.~~

== References ==

~~-->~~

~~{{ABSTRACT_PUBMED_19358611}}~~

__TOC__

</StructureSection>

==~~About this Structure~~==

~~3G72 is a 2 chains structure of sequences 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=3G72 OCA~~].

==~~Reference~~==

<~~ref group="xtra">PMID:19358611<~~/~~ref~~><~~references group="xtra"~~/>

[[Category: Homo sapiens]]

[[Category: ~~Renin~~]]

[[Category: Large Structures]]

[[Category: Bezencon, O.]]

[[Category: Bezencon O]]

[[Category: Boss, C.]]

[[Category: Boss C]]

[[Category: Bur, D.]]

[[Category: Bur D]]

[[Category: Fischli, W.]]

[[Category: Fischli W]]

[[Category: Prade, L.]]

[[Category: Prade L]]

[[Category: Weller, T.]]

[[Category: Weller T]]

~~[[Category: Alternative splicing]]~~

~~[[Category: Aspartyl protease]]~~

~~[[Category: Cleavage on pair of basic residue]]~~

~~[[Category: Disease mutation]]~~

~~[[Category: Glycoprotein]]~~

~~[[Category: Hydrolase]]~~

~~[[Category: Membrane]]~~

~~[[Category: Polymorphism]]~~

~~[[Category: Protease]]~~

~~[[Category: Renin human]]~~

~~[[Category: Secreted]]~~

~~[[Category: Zymogen]]~~

~~''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 1 09:15:34 2009''~~

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@@ Line 1: / Line 1: @@
-{{Seed}}
-[[Image:3g72.jpg|left|200px]]
-<!--
+==Design and Preparation of Potent, Non-Peptidic, Bioavailable Renin Inhibitors==
-The line below this paragraph, containing "STRUCTURE_3g72", creates the "Structure Box" on the page.
+<StructureSection load='3g72' size='340' side='right'caption='[[3g72]], [[Resolution|resolution]] 1.90&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'>[[3g72]] 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=3G72 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G72 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]] 1.9&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A6T:(1S,5R)-7-{4-[3-(2-CHLORO-3,6-DIFLUOROPHENOXY)PROPYL]PHENYL}-N-CYCLOPROPYL-N-(2,3-DICHLOROBENZYL)-3,9-DIAZABICYCLO[3.3.1]NON-6-ENE-6-CARBOXAMIDE'>A6T</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-{{STRUCTURE_3g72|  PDB=3g72  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3g72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g72 OCA], [https://pdbe.org/3g72 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g72 RCSB], [https://www.ebi.ac.uk/pdbsum/3g72 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g72 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.
+== 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/g7/3g72_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=3g72 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
-===Design and Preparation of Potent, Non-Peptidic, Bioavailable Renin Inhibitors===
+Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.,Bezencon O, Bur D, Weller T, Richard-Bildstein S, Remen L, Sifferlen T, Corminboeuf O, Grisostomi C, Boss C, Prade L, Delahaye S, Treiber A, Strickner P, Binkert C, Hess P, Steiner B, Fischli W J Med Chem. 2009 Jun 25;52(12):3689-702. PMID:19358611<ref>PMID:19358611</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3g72" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_19358611}}, adds the Publication Abstract to the page
+*[[Renin|Renin]]
-(as it appears on PubMed at http://www.pubmed.gov), where 19358611 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_19358611}}
+__TOC__
+</StructureSection>
-==About this Structure==
-G72 is a 2 chains structure of sequences 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=3G72 OCA].
-==Reference==
-<ref group="xtra">PMID:19358611</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
-[[Category: Renin]]
+[[Category: Large Structures]]
-[[Category: Bezencon, O.]]
+[[Category: Bezencon O]]
-[[Category: Boss, C.]]
+[[Category: Boss C]]
-[[Category: Bur, D.]]
+[[Category: Bur D]]
-[[Category: Fischli, W.]]
+[[Category: Fischli W]]
-[[Category: Prade, L.]]
+[[Category: Prade L]]
-[[Category: Weller, T.]]
+[[Category: Weller T]]
-[[Category: Alternative splicing]]
-[[Category: Aspartyl protease]]
-[[Category: Cleavage on pair of basic residue]]
-[[Category: Disease mutation]]
-[[Category: Glycoprotein]]
-[[Category: Hydrolase]]
-[[Category: Membrane]]
-[[Category: Polymorphism]]
-[[Category: Protease]]
-[[Category: Renin human]]
-[[Category: Secreted]]
-[[Category: Zymogen]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul  1 09:15:34 2009''