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[[Image:8est.gif|left|200px]]


{{Structure
==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==
|PDB= 8est |SIZE=350|CAPTION= <scene name='initialview01'>8est</scene>, resolution 1.78&Aring;
<StructureSection load='8est' size='340' side='right'caption='[[8est]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <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>
<table><tr><td colspan='2'>[[8est]] is a 1 chain structure with sequence from [https://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]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8EST FirstGlance]. <br>
|ACTIVITY= <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><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.78&#8491;</td></tr>
|GENE=
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8est FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8est OCA], [https://pdbe.org/8est PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8est RCSB], [https://www.ebi.ac.uk/pdbsum/8est PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8est ProSAT]</span></td></tr>
|RELATEDENTRY=
</table>
|RESOURCES=<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://www.ebi.ac.uk/pdbsum/8est PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=8est RCSB]</span>
== Function ==
}}
[https://www.uniprot.org/uniprot/CELA1_PIG CELA1_PIG] Acts upon elastin.
== 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/es/8est_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=8est ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


'''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'''
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>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8est" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
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.
*[[Elastase 3D structures|Elastase 3D structures]]
 
== References ==
==About this Structure==
<references/>
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].
__TOC__
 
</StructureSection>
==Reference==
[[Category: Large Structures]]
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]
[[Category: Pancreatic elastase]]
[[Category: Single protein]]
[[Category: Sus scrofa]]
[[Category: Sus scrofa]]
[[Category: Meyerjunior, E F.]]
[[Category: Meyerjunior EF]]
[[Category: Powers, J C.]]
[[Category: Powers JC]]
[[Category: Radhakrishnan, R.]]
[[Category: Radhakrishnan R]]
[[Category: hydrolase(serine proteinase)]]
 
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