8est

From Proteopedia

(Difference between revisions)

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

Structural highlights

8est is a 1 chain structure with sequence from Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.78Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CELA1_PIG Acts upon elastin.

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

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the previously reported structure of the 7-amino-4-chloro-3-methoxyisocoumarin-PPE complex where the chlorine atom has been replaced by an acetoxy group.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-guanidinoisocoumarin.,Powers JC, Oleksyszyn J, Narasimhan SL, Kam CM Biochemistry. 1990 Mar 27;29(12):3108-18. PMID:2337582^[1]

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

References

↑ Powers JC, Oleksyszyn J, Narasimhan SL, Kam CM. 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. Biochemistry. 1990 Mar 27;29(12):3108-18. PMID:2337582

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8est"

Categories: Large Structures | Sus scrofa | Meyerjunior EF | Powers JC | Radhakrishnan R

@@ Line 1: / Line 1: @@
 ==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==
-<StructureSection load='8est' size='340' side='right' caption='[[8est]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
+<StructureSection load='8est' size='340' side='right'caption='[[8est]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<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>
-</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>
+</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>
-<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>
+<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>
-<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>
+<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>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/CELA1_PIG CELA1_PIG]] Acts upon elastin.
+[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>
+    <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>
@@ Line 31: / Line 31: @@
 ==See Also==
-*[[Elastase|Elastase]]
+*[[Elastase 3D structures|Elastase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Pancreatic elastase]]
+[[Category: Large Structures]]
-[[Category: Pig]]
+[[Category: Sus scrofa]]
-[[Category: Meyerjunior, E F]]
+[[Category: Meyerjunior EF]]
-[[Category: Powers, J C]]
+[[Category: Powers JC]]
-[[Category: Radhakrishnan, R]]
+[[Category: Radhakrishnan R]]

8est

From Proteopedia

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

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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