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| | {{STRUCTURE_1u3t| PDB=1u3t | SCENE= }} | | {{STRUCTURE_1u3t| PDB=1u3t | SCENE= }} |
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| - | '''Crystal Structure of Human Alcohol Dehydrogenase Alpha-Alpha Isoform Complexed with N-Cyclopentyl-N-Cyclobutylformamide Determined to 2.5 Angstrom Resolution'''
| + | ===Crystal Structure of Human Alcohol Dehydrogenase Alpha-Alpha Isoform Complexed with N-Cyclopentyl-N-Cyclobutylformamide Determined to 2.5 Angstrom Resolution=== |
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| - | ==Overview==
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| - | Formamides are aldehyde analogues that have demonstrated potent and selective inhibition of human alcohol dehydrogenase isoenzymes. The alphaalpha, beta(1)beta(1), gamma(2)gamma(2), and sigmasigma isoforms have all been found to be strongly inhibited by substituted formamides. In this paper, the structure of the alphaalpha isoform of human alcohol dehydrogenase complexed with N-cyclopentyl-N-cyclobutylformamide was determined by X-ray crystallography to 2.5 A resolution, the beta(1)beta(1) isoform of human alcohol dehydrogenase complexed with N-benzylformamide and with N-heptylformamide was determined to 1.6 and 1.65 A resolution, respectively, and the structure of the gamma(2)gamma(2) isoform complexed with N-1-methylheptylformamide was determined to 1.45 A resolution. These structures provide the first substrate-level view of the local structural differences that give rise to the individual substrate preferences shown by these highly related isoenzymes. Consistent with previous work, the carbonyl oxygen of the inhibitors interacts directly with the catalytic zinc and the hydroxyl group of Thr48 (Ser48 for gamma(2)gamma(2)) of the enzyme. The benzene ring of N-benzylformamide and the carbon chains of N-heptylformamide and N-1-methylheptylformamide interact with the sides of the hydrophobic substrate pocket whose size and shape is dictated by residue exchanges between the beta(1)beta(1) and gamma(2)gamma(2) isoenzymes. In particular, the exchange of Ser for Thr at position 48 and the exchange of Val for Leu at position 141 in the gamma(2)gamma(2) isoenzyme create an environment with stereoselectivity for the R-enantiomer of the branched N-1-methylheptylformamide inhibitor in this isoenzyme. The primary feature of the alphaalpha isoform is the Ala for Phe93 exchange that enlarges the active site near the catalytic zinc and creates the specificity for the branched N-cyclopentyl-N-cyclobutylformamide inhibitor, which shows the greatest selectivity for this unique isoenzyme of any of the formamide inhibitors.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_15449945}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 15449945 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_15449945}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Hurley, T D.]] | | [[Category: Hurley, T D.]] |
| | [[Category: Oxidoreductase]] | | [[Category: Oxidoreductase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 10:43:43 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 18:53:03 2008'' |
Revision as of 15:53, 27 July 2008
Template:STRUCTURE 1u3t
Crystal Structure of Human Alcohol Dehydrogenase Alpha-Alpha Isoform Complexed with N-Cyclopentyl-N-Cyclobutylformamide Determined to 2.5 Angstrom Resolution
Template:ABSTRACT PUBMED 15449945
About this Structure
1U3T is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure of three class I human alcohol dehydrogenases complexed with isoenzyme specific formamide inhibitors., Gibbons BJ, Hurley TD, Biochemistry. 2004 Oct 5;43(39):12555-62. PMID:15449945
Page seeded by OCA on Sun Jul 27 18:53:03 2008
