1zd5
From Proteopedia
(New page: 200px<br /> <applet load="1zd5" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zd5, resolution 2.6Å" /> '''Human soluble epoxid...) |
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| - | [[Image:1zd5.gif|left|200px]]<br /> | + | [[Image:1zd5.gif|left|200px]]<br /><applet load="1zd5" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1zd5" size=" | + | |
caption="1zd5, resolution 2.6Å" /> | caption="1zd5, resolution 2.6Å" /> | ||
'''Human soluble epoxide hydrolase 4-(3-cyclohexyluriedo)-heptanoic acid complex'''<br /> | '''Human soluble epoxide hydrolase 4-(3-cyclohexyluriedo)-heptanoic acid complex'''<br /> | ||
==Overview== | ==Overview== | ||
| - | X-ray crystal structures of human soluble epoxide hydrolase (sEH) | + | X-ray crystal structures of human soluble epoxide hydrolase (sEH) complexed with four different dialkylurea inhibitors bearing pendant carboxylate "tails" of varying length have been determined at 2.3-3.0 A resolution. Similarities among inhibitor binding modes reinforce the proposed roles of Y381 and/or Y465 as general acids that protonate the epoxide ring of the substrate in concert with nucleophilic attack of D333 at the electrophilic epoxide carbon. Additionally, the binding of these inhibitors allows us to model the binding mode of the endogenous substrate 14,15-epoxyeicosatrienoic acid. Contrasts among inhibitor binding modes include opposite orientations of inhibitor binding in the active-site hydrophobic tunnel. Alternative binding orientations observed for this series of inhibitors to human sEH, as well as the binding of certain dialkylurea inhibitors to human sEH and murine sEH, complicate the structure-based design of human sEH inhibitors with potential pharmaceutical applications in the treatment of hypertension. Thus, with regard to the optimization of inhibitor designs targeting human sEH, it is critical that human sEH and not murine sEH be utilized for inhibitor screening, and it is critical that structures of human sEH-inhibitor complexes be determined to verify inhibitor binding orientations that correlate with measured affinities. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1ZD5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, PO4 and NC7 as [http://en.wikipedia.org/wiki/ligands ligands]. 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:// | + | 1ZD5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=PO4:'>PO4</scene> and <scene name='pdbligand=NC7:'>NC7</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=1ZD5 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Microsomal epoxide hydrolase]] | [[Category: Microsomal epoxide hydrolase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Christianson, D | + | [[Category: Christianson, D W.]] |
| - | [[Category: Gomez, G | + | [[Category: Gomez, G A.]] |
| - | [[Category: Hammock, B | + | [[Category: Hammock, B D.]] |
[[Category: Morisseau, C.]] | [[Category: Morisseau, C.]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: domain-swapped dimer]] | [[Category: domain-swapped dimer]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:14:23 2008'' |
Revision as of 14:14, 21 February 2008
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Human soluble epoxide hydrolase 4-(3-cyclohexyluriedo)-heptanoic acid complex
Contents |
Overview
X-ray crystal structures of human soluble epoxide hydrolase (sEH) complexed with four different dialkylurea inhibitors bearing pendant carboxylate "tails" of varying length have been determined at 2.3-3.0 A resolution. Similarities among inhibitor binding modes reinforce the proposed roles of Y381 and/or Y465 as general acids that protonate the epoxide ring of the substrate in concert with nucleophilic attack of D333 at the electrophilic epoxide carbon. Additionally, the binding of these inhibitors allows us to model the binding mode of the endogenous substrate 14,15-epoxyeicosatrienoic acid. Contrasts among inhibitor binding modes include opposite orientations of inhibitor binding in the active-site hydrophobic tunnel. Alternative binding orientations observed for this series of inhibitors to human sEH, as well as the binding of certain dialkylurea inhibitors to human sEH and murine sEH, complicate the structure-based design of human sEH inhibitors with potential pharmaceutical applications in the treatment of hypertension. Thus, with regard to the optimization of inhibitor designs targeting human sEH, it is critical that human sEH and not murine sEH be utilized for inhibitor screening, and it is critical that structures of human sEH-inhibitor complexes be determined to verify inhibitor binding orientations that correlate with measured affinities.
Disease
Known disease associated with this structure: Hypercholesterolemia, familial, due to LDLR defect, modifier of OMIM:[132811]
About this Structure
1ZD5 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Microsomal epoxide hydrolase, with EC number 3.3.2.9 Full crystallographic information is available from OCA.
Reference
Human soluble epoxide hydrolase: structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids., Gomez GA, Morisseau C, Hammock BD, Christianson DW, Protein Sci. 2006 Jan;15(1):58-64. Epub 2005 Dec 1. PMID:16322563
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