1d1s
From Proteopedia
| Line 1: | Line 1: | ||
[[Image:1d1s.gif|left|200px]] | [[Image:1d1s.gif|left|200px]] | ||
| - | + | <!-- | |
| - | + | The line below this paragraph, containing "STRUCTURE_1d1s", creates the "Structure Box" on the page. | |
| - | + | You may change the PDB parameter (which sets the PDB file loaded into the applet) | |
| - | + | or the SCENE parameter (which sets the initial scene displayed when the page is loaded), | |
| - | + | or leave the SCENE parameter empty for the default display. | |
| - | | | + | --> |
| - | | | + | {{STRUCTURE_1d1s| PDB=1d1s | SCENE= }} |
| - | + | ||
| - | + | ||
| - | }} | + | |
'''WILD-TYPE HUMAN SIGMA (CLASS IV) ALCOHOL DEHYDROGENASE''' | '''WILD-TYPE HUMAN SIGMA (CLASS IV) ALCOHOL DEHYDROGENASE''' | ||
| Line 28: | Line 25: | ||
[[Category: Hurley, T D.]] | [[Category: Hurley, T D.]] | ||
[[Category: Xie, P T.]] | [[Category: Xie, P T.]] | ||
| - | [[Category: | + | [[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 | + | |
Revision as of 10:21, 2 May 2008
WILD-TYPE HUMAN SIGMA (CLASS IV) ALCOHOL DEHYDROGENASE
Overview
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.
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 Fri May 2 13:21:07 2008
