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| | {{STRUCTURE_1j79| PDB=1j79 | SCENE= }} | | {{STRUCTURE_1j79| PDB=1j79 | SCENE= }} |
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| - | '''Molecular Structure of Dihydroorotase: A Paradigm for Catalysis Through the Use of a Binuclear Metal Center'''
| + | ===Molecular Structure of Dihydroorotase: A Paradigm for Catalysis Through the Use of a Binuclear Metal Center=== |
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| - | ==Overview==
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| - | Dihydroorotase plays a key role in pyrimidine biosynthesis by catalyzing the reversible interconversion of carbamoyl aspartate to dihydroorotate. Here we describe the three-dimensional structure of dihydroorotase from Escherichia coli determined and refined to 1.7 A resolution. Each subunit of the homodimeric enzyme folds into a "TIM" barrel motif with eight strands of parallel beta-sheet flanked on the outer surface by alpha-helices. Unexpectedly, each subunit contains a binuclear zinc center with the metal ions separated by approximately 3.6 A. Lys 102, which is carboxylated, serves as a bridging ligand between the two cations. The more buried or alpha-metal ion in subunit I is surrounded by His 16, His 18, Lys 102, Asp 250, and a solvent molecule (most likely a hydroxide ion) in a trigonal bipyramidal arrangement. The beta-metal ion, which is closer to the solvent, is tetrahedrally ligated by Lys 102, His 139, His 177, and the bridging hydroxide. L-Dihydroorotate is observed bound to subunit I, with its carbonyl oxygen, O4, lying 2.9 A from the beta-metal ion. Important interactions for positioning dihydroorotate into the active site include a salt bridge with the guanidinium group of Arg 20 and various additional electrostatic interactions with both protein backbone and side chain atoms. Strikingly, in subunit II, carbamoyl L-aspartate is observed binding near the binuclear metal center with its carboxylate side chain ligating the two metals and thus displacing the bridging hydroxide ion. From the three-dimensional structures of the enzyme-bound substrate and product, it has been possible to propose a unique catalytic mechanism for dihydroorotase. In the direction of dihydroorotate hydrolysis, the bridging hydroxide attacks the re-face of dihydroorotate with general base assistance by Asp 250. The carbonyl group is polarized for nucleophilic attack by the bridging hydroxide through a direct interaction with the beta-metal ion. During the cyclization of carbamoyl aspartate, Asp 250 initiates the reaction by abstracting a proton from N3 of the substrate. The side chain carboxylate of carbamoyl aspartate is polarized through a direct electrostatic interaction with the binuclear metal center. The ensuing tetrahedral intermediate collapses with C-O bond cleavage and expulsion of the hydroxide which then bridges the binuclear metal center.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_11401542}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11401542 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_11401542}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Pyrimidine biosynthesis]] | | [[Category: Pyrimidine biosynthesis]] |
| | [[Category: Tim barrel]] | | [[Category: Tim barrel]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 20:52:09 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 14:34:34 2008'' |
Revision as of 11:34, 1 July 2008
Template:STRUCTURE 1j79
Molecular Structure of Dihydroorotase: A Paradigm for Catalysis Through the Use of a Binuclear Metal Center
Template:ABSTRACT PUBMED 11401542
About this Structure
1J79 is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
Molecular structure of dihydroorotase: a paradigm for catalysis through the use of a binuclear metal center., Thoden JB, Phillips GN Jr, Neal TM, Raushel FM, Holden HM, Biochemistry. 2001 Jun 19;40(24):6989-97. PMID:11401542
Page seeded by OCA on Tue Jul 1 14:34:34 2008
