1ek2
From Proteopedia
(New page: 200px<br /><applet load="1ek2" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ek2, resolution 3.0Å" /> '''CRYSTAL STRUCTURE OF ...) |
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| - | [[Image:1ek2.gif|left|200px]]<br /><applet load="1ek2" size=" | + | [[Image:1ek2.gif|left|200px]]<br /><applet load="1ek2" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1ek2, resolution 3.0Å" /> | caption="1ek2, resolution 3.0Å" /> | ||
'''CRYSTAL STRUCTURE OF MURINE SOLUBLE EPOXIDE HYDROLASE COMPLEXED WITH CDU INHIBITOR'''<br /> | '''CRYSTAL STRUCTURE OF MURINE SOLUBLE EPOXIDE HYDROLASE COMPLEXED WITH CDU INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The structures of two alkylurea inhibitors complexed with murine soluble | + | The structures of two alkylurea inhibitors complexed with murine soluble epoxide hydrolase have been determined by x-ray crystallographic methods. The alkyl substituents of each inhibitor make extensive hydrophobic contacts in the soluble epoxide hydrolase active site, and each urea carbonyl oxygen accepts hydrogen bonds from the phenolic hydroxyl groups of Tyr(381) and Tyr(465). These hydrogen bond interactions suggest that Tyr(381) and/or Tyr(465) are general acid catalysts that facilitate epoxide ring opening in the first step of the hydrolysis reaction; Tyr(465) is highly conserved among all epoxide hydrolases, and Tyr(381) is conserved among the soluble epoxide hydrolases. In one enzyme-inhibitor complex, the urea carbonyl oxygen additionally interacts with Gln(382). If a comparable interaction occurs in catalysis, then Gln(382) may provide electrostatic stabilization of partial negative charge on the epoxide oxygen. The carboxylate side chain of Asp(333) accepts a hydrogen bond from one of the urea NH groups in each enzyme-inhibitor complex. Because Asp(333) is the catalytic nucleophile, its interaction with the partial positive charge on the urea NH group mimics its approach toward the partial positive charge on the electrophilic carbon of an epoxide substrate. Accordingly, alkylurea inhibitors mimic features encountered in the reaction coordinate of epoxide ring opening, and a structure-based mechanism is proposed for leukotoxin epoxide hydrolysis. |
==About this Structure== | ==About this Structure== | ||
| - | 1EK2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with CDU as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Microsomal_epoxide_hydrolase Microsomal epoxide hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.2.9 3.3.2.9] Full crystallographic information is available from [http:// | + | 1EK2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=CDU:'>CDU</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Microsomal_epoxide_hydrolase Microsomal epoxide hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.2.9 3.3.2.9] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EK2 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Argiriadi, M | + | [[Category: Argiriadi, M A.]] |
| - | [[Category: Christianson, D | + | [[Category: Christianson, D W.]] |
| - | [[Category: Dowdy, D | + | [[Category: Dowdy, D L.]] |
| - | [[Category: Goodrow, M | + | [[Category: Goodrow, M H.]] |
| - | [[Category: Hammock, B | + | [[Category: Hammock, B D.]] |
[[Category: Morisseau, C.]] | [[Category: Morisseau, C.]] | ||
[[Category: CDU]] | [[Category: CDU]] | ||
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[[Category: homodimer]] | [[Category: homodimer]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:28:38 2008'' |
Revision as of 10:28, 21 February 2008
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CRYSTAL STRUCTURE OF MURINE SOLUBLE EPOXIDE HYDROLASE COMPLEXED WITH CDU INHIBITOR
Overview
The structures of two alkylurea inhibitors complexed with murine soluble epoxide hydrolase have been determined by x-ray crystallographic methods. The alkyl substituents of each inhibitor make extensive hydrophobic contacts in the soluble epoxide hydrolase active site, and each urea carbonyl oxygen accepts hydrogen bonds from the phenolic hydroxyl groups of Tyr(381) and Tyr(465). These hydrogen bond interactions suggest that Tyr(381) and/or Tyr(465) are general acid catalysts that facilitate epoxide ring opening in the first step of the hydrolysis reaction; Tyr(465) is highly conserved among all epoxide hydrolases, and Tyr(381) is conserved among the soluble epoxide hydrolases. In one enzyme-inhibitor complex, the urea carbonyl oxygen additionally interacts with Gln(382). If a comparable interaction occurs in catalysis, then Gln(382) may provide electrostatic stabilization of partial negative charge on the epoxide oxygen. The carboxylate side chain of Asp(333) accepts a hydrogen bond from one of the urea NH groups in each enzyme-inhibitor complex. Because Asp(333) is the catalytic nucleophile, its interaction with the partial positive charge on the urea NH group mimics its approach toward the partial positive charge on the electrophilic carbon of an epoxide substrate. Accordingly, alkylurea inhibitors mimic features encountered in the reaction coordinate of epoxide ring opening, and a structure-based mechanism is proposed for leukotoxin epoxide hydrolysis.
About this Structure
1EK2 is a Single protein structure of sequence from Mus musculus with as ligand. Active as Microsomal epoxide hydrolase, with EC number 3.3.2.9 Full crystallographic information is available from OCA.
Reference
Binding of alkylurea inhibitors to epoxide hydrolase implicates active site tyrosines in substrate activation., Argiriadi MA, Morisseau C, Goodrow MH, Dowdy DL, Hammock BD, Christianson DW, J Biol Chem. 2000 May 19;275(20):15265-70. PMID:10747889
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