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| - | [[Image:1d1s.gif|left|200px]] | + | {{Seed}} |
| | + | [[Image:1d1s.png|left|200px]] |
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| | {{STRUCTURE_1d1s| PDB=1d1s | SCENE= }} | | {{STRUCTURE_1d1s| PDB=1d1s | SCENE= }} |
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| - | '''WILD-TYPE HUMAN SIGMA (CLASS IV) ALCOHOL DEHYDROGENASE'''
| + | ===WILD-TYPE HUMAN SIGMA (CLASS IV) ALCOHOL DEHYDROGENASE=== |
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| - | ==Overview==
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| - | Pyrazole and its 4-alkyl substituted derivatives are potent inhibitors for many alcohol dehydrogenases. However, the human sigma sigma isoenzyme exhibits a 580-fold lower affinity for 4-methylpyrazole than does the human beta1beta1 isoenzyme, with which it shares 69% sequence identity. In this study, structural and kinetic studies were utilized in an effort to identify key structural features that affect the binding of 4-methylpyrazole in human alcohol dehydrogenase isoenzymes. We have extended the resolution of the human sigma sigma alcohol dehydrogenase (ADH) isoenzyme to 2.5 A resolution. Comparison of this structure to the human beta1beta1 isoenzyme structure indicated that the side-chain position for Met141 in sigma sigma ADH might interfere with 4-methylpyrazole binding. Mutation of Met141 in sigma sigma ADH to Leu (sigma141L) lowers the Ki for 4-methylpyrazole from 350 to 10 microM, while having a much smaller effect on the Ki for pyrazole. Thus, the mutagenesis results show that the residue at position 141, which lines the substrate-binding pocket at a position close to the methyl group of 4-methylpyrazole, directly affects the binding of the inhibitor. To rule out nonspecific structural changes due to the mutation, the X-ray structure of the sigma141L mutant enzyme was determined to 2.4 A resolution. The three-dimensional structure of the mutant enzyme is identical to the wild-type enzyme, with the exception of the residue at position 141. Thus, the differences in 4-methylpyrazole binding between the mutant and wild-type sigma sigma ADH isoenzymes can be completely ascribed to the local changes in the topology of the substrate binding site, and provides an explanation for the class-specific differences in 4-methylpyrazole binding to the human ADH isoenzymes.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10631979}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10631979 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10631979}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Xie, P T.]] | | [[Category: Xie, P T.]] |
| | [[Category: Rossman or dinucleotide fold]] | | [[Category: Rossman or dinucleotide fold]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 13:21:07 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 22:07:17 2008'' |
Revision as of 19:07, 30 June 2008
Template:STRUCTURE 1d1s
WILD-TYPE HUMAN SIGMA (CLASS IV) ALCOHOL DEHYDROGENASE
Template:ABSTRACT PUBMED 10631979
About this Structure
1D1S is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Methionine-141 directly influences the binding of 4-methylpyrazole in human sigma sigma alcohol dehydrogenase., Xie PT, Hurley TD, Protein Sci. 1999 Dec;8(12):2639-44. PMID:10631979
Page seeded by OCA on Mon Jun 30 22:07:17 2008
