2iku: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-{{Seed}}
-[[Image:2iku.png|left|200px]]
-<!--
+==Crystal Structure of Human Renin Complexed with Inhibitors==
-The line below this paragraph, containing "STRUCTURE_2iku", creates the "Structure Box" on the page.
+<StructureSection load='2iku' size='340' side='right'caption='[[2iku]], [[Resolution|resolution]] 2.60&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'>[[2iku]] 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=2IKU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IKU 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]] 2.6&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LIY:6-ETHYL-5-[(2S)-1-(3-METHOXYPROPYL)-2-PHENYL-1,2,3,4-TETRAHYDROQUINOLIN-7-YL]PYRIMIDINE-2,4-DIAMINE'>LIY</scene></td></tr>
-{{STRUCTURE_2iku|  PDB=2iku  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2iku FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iku OCA], [https://pdbe.org/2iku PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2iku RCSB], [https://www.ebi.ac.uk/pdbsum/2iku PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2iku 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/ik/2iku_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=2iku ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.
-===Crystal Structure of Human Renin Complexed with Inhibitors===
+Binding thermodynamics of substituted diaminopyrimidine renin inhibitors.,Sarver RW, Peevers J, Cody WL, Ciske FL, Dyer J, Emerson SD, Hagadorn JC, Holsworth DD, Jalaie M, Kaufman M, Mastronardi M, McConnell P, Powell NA, Quin J 3rd, Van Huis CA, Zhang E, Mochalkin I Anal Biochem. 2007 Jan 1;360(1):30-40. Epub 2006 Oct 30. PMID:17113558<ref>PMID:17113558</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2iku" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_17113558}}, adds the Publication Abstract to the page
+*[[Renin|Renin]]
-(as it appears on PubMed at http://www.pubmed.gov), where 17113558 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_17113558}}
+__TOC__
+</StructureSection>
-==About this Structure==
-IKU 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=2IKU OCA].
-==Reference==
-Binding thermodynamics of substituted diaminopyrimidine renin inhibitors., Sarver RW, Peevers J, Cody WL, Ciske FL, Dyer J, Emerson SD, Hagadorn JC, Holsworth DD, Jalaie M, Kaufman M, Mastronardi M, McConnell P, Powell NA, Quin J 3rd, Van Huis CA, Zhang E, Mochalkin I, Anal Biochem. 2007 Jan 1;360(1):30-40. Epub 2006 Oct 30. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17113558 17113558]
 [[Category: Homo sapiens]]
-[[Category: Renin]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Mochalkin I]]
-[[Category: Mochalkin, I.]]
-[[Category: Drug design]]
-[[Category: Inhibitor]]
-[[Category: Renin]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 04:54:51 2008''