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| | {{STRUCTURE_8est| PDB=8est | SCENE= }} | | {{STRUCTURE_8est| PDB=8est | SCENE= }} |
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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'''
| + | ===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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| - | ==Overview==
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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the previously reported structure of the 7-amino-4-chloro-3-methoxyisocoumarin-PPE complex where the chlorine atom has been replaced by an acetoxy group.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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_2337582}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 2337582 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_2337582}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Powers, J C.]] | | [[Category: Powers, J C.]] |
| | [[Category: Radhakrishnan, R.]] | | [[Category: Radhakrishnan, R.]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 22:49:07 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Jul 11 12:56:25 2008'' |
Revision as of 09:56, 11 July 2008
Template:STRUCTURE 8est
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
Template:ABSTRACT PUBMED 2337582
About this Structure
8EST is a Single protein structure of sequence from Sus scrofa. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Fri Jul 11 12:56:25 2008
