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8est

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{{Seed}}
 
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[[Image:8est.png|left|200px]]
 
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==REACTION OF PORCINE PANCREATIC ELASTASE WITH 7-SUBSTITUTED 3-ALKOXY-4-CHLOROISOCOUMARINS: DESIGN OF POTENT INHIBITORS USING THE CRYSTAL STRUCTURE OF THE COMPLEX FORMED WITH 4-CHLORO-3-ETHOXY-7-GUANIDINO-ISOCOUMARIN==
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The line below this paragraph, containing "STRUCTURE_8est", creates the "Structure Box" on the page.
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<StructureSection load='8est' size='340' side='right' caption='[[8est]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[8est]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pig Pig]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8EST OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=8EST FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GIS:ETHYL-(2-CARBOXY-4-GUANIDINIUM-PHENYL)-CHLOROACETATE'>GIS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pancreatic_elastase Pancreatic elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.36 3.4.21.36] </span></td></tr>
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{{STRUCTURE_8est| PDB=8est | SCENE= }}
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<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=8est FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8est OCA], [http://pdbe.org/8est PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=8est RCSB], [http://www.ebi.ac.uk/pdbsum/8est PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=8est ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/CELA1_PIG CELA1_PIG]] Acts upon elastin.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/es/8est_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=8est ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The crystal structure of the acyl enzyme formed upon inhibition of porcine pancreatic elastase (PPE) by 4-chloro-3-ethoxy-7-guanidinoisocoumarin has been determined at a 1.85-A effective resolution. The chlorine atom is still present in this acyl enzyme, in contrast to the previously reported structure of the 7-amino-4-chloro-3-methoxyisocoumarin-PPE complex where the chlorine atom has been replaced by an acetoxy group. The guanidino group forms hydrogen bonds with the carbonyl group and side-chain hydroxyl group of Thr-41, and the acyl carbonyl group has been twisted out of the oxyanion hole. Molecular modeling indicates that the orientation of the initial Michaelis enzyme-inhibitor complex is quite different from that of the acyl enzyme since simple reconstruction of the isocoumarin ring would result in unfavorable interactions with Ser-195 and His-57. Molecular models were used to design a series of new 7-(alkylureido)- and 7-(alkylthioureido)-substituted derivatives of 3-alkoxy-7-amino-4-chloroisocoumarin as PPE inhibitors. All the 3-ethoxyisocoumarins were better inhibitors than those in the 3-methoxy series due to better interactions with the S1 pocket of PPE. The best ureido inhibitor also contained a tert-butylureido group at the 7-position of the isocoumarin. Due to a predicted interaction with a small hydrophobic pocket on the surface of PPE, this isocoumarin and a related phenylthioureido derivative are among the best irreversible inhibitors thus far reported for PPE (kobs/[I] = 8100 M-1 s-1 and 12,000 M-1 s-1). Kinetic studies of the stability of enzyme-inhibitor complexes suggest that many isocoumarins are alkylating the active site histidine at pH 7.5 via a quinone imine methide intermediate, while at pH 5.0, the predominant pathway appears to be simple formation of a stable acyl enzyme derivative.
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===REACTION OF PORCINE PANCREATIC ELASTASE WITH 7-SUBSTITUTED 3-ALKOXY-4-CHLOROISOCOUMARINS: DESIGN OF POTENT INHIBITORS USING THE CRYSTAL STRUCTURE OF THE COMPLEX FORMED WITH 4-CHLORO-3-ETHOXY-7-GUANIDINO-ISOCOUMARIN===
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Reaction of porcine pancreatic elastase with 7-substituted 3-alkoxy-4-chloroisocoumarins: design of potent inhibitors using the crystal structure of the complex formed with 4-chloro-3-ethoxy-7-guanidinoisocoumarin.,Powers JC, Oleksyszyn J, Narasimhan SL, Kam CM Biochemistry. 1990 Mar 27;29(12):3108-18. PMID:2337582<ref>PMID:2337582</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 8est" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_2337582}}, adds the Publication Abstract to the page
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*[[Elastase|Elastase]]
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(as it appears on PubMed at http://www.pubmed.gov), where 2337582 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_2337582}}
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__TOC__
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</StructureSection>
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==About this Structure==
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8EST is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8EST OCA].
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==Reference==
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Reaction of porcine pancreatic elastase with 7-substituted 3-alkoxy-4-chloroisocoumarins: design of potent inhibitors using the crystal structure of the complex formed with 4-chloro-3-ethoxy-7-guanidinoisocoumarin., Powers JC, Oleksyszyn J, Narasimhan SL, Kam CM, Biochemistry. 1990 Mar 27;29(12):3108-18. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/2337582 2337582]
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[[Category: Pancreatic elastase]]
[[Category: Pancreatic elastase]]
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[[Category: Single protein]]
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[[Category: Pig]]
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[[Category: Sus scrofa]]
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[[Category: Meyerjunior, E F]]
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[[Category: Meyerjunior, E F.]]
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[[Category: Powers, J C]]
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[[Category: Powers, J C.]]
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[[Category: Radhakrishnan, R]]
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[[Category: Radhakrishnan, R.]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Jul 11 12:56:25 2008''
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Current revision

REACTION OF PORCINE PANCREATIC ELASTASE WITH 7-SUBSTITUTED 3-ALKOXY-4-CHLOROISOCOUMARINS: DESIGN OF POTENT INHIBITORS USING THE CRYSTAL STRUCTURE OF THE COMPLEX FORMED WITH 4-CHLORO-3-ETHOXY-7-GUANIDINO-ISOCOUMARIN

8est, resolution 1.78Å

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