2001
DOI: 10.1021/bi0155908
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Long-Range Interactions in the Dimer Interface of Ornithine Decarboxylase Are Important for Enzyme Function

Abstract: Ornithine decarboxylase (ODC) is a pyridoxal 5'-phosphate dependent enzyme that catalyzes the first committed step in the biosynthesis of polyamines. ODC is a proven drug target for the treatment of African sleeping sickness. The enzyme is an obligate homodimer, and the two identical active sites are formed at the dimer interface. Alanine scanning mutagenesis of dimer interface residues in Trypanosoma brucei ODC was undertaken to determine the energetic contribution of these residues to subunit association. Tw… Show more

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Cited by 40 publications
(57 citation statements)
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“…The results obtained indicate that such low affinity is partly due to the presence of several side chains in the contact epitope (Ser-178, Glu-180, Glu-187, and especially Gln-192) that not only do not favor association but that individually decrease the association constant up to more than one order of magnitude. An increase in affinity has been rarely found upon mutation of residues in other protein-protein interfaces, and when encountered, this effect was generally very small (5,8,15,21). The interfacial residues that negatively affect affinity, and/or the interactions they make, including possible electrostatic repulsions at opposite sides of the interface rim (see "Results"), appeared highly conserved in HIV, even more than some of the critical residues in the energetic epitope.…”
Section: Discussionmentioning
confidence: 99%
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“…The results obtained indicate that such low affinity is partly due to the presence of several side chains in the contact epitope (Ser-178, Glu-180, Glu-187, and especially Gln-192) that not only do not favor association but that individually decrease the association constant up to more than one order of magnitude. An increase in affinity has been rarely found upon mutation of residues in other protein-protein interfaces, and when encountered, this effect was generally very small (5,8,15,21). The interfacial residues that negatively affect affinity, and/or the interactions they make, including possible electrostatic repulsions at opposite sides of the interface rim (see "Results"), appeared highly conserved in HIV, even more than some of the critical residues in the energetic epitope.…”
Section: Discussionmentioning
confidence: 99%
“…Mutation to Ala of residues other than Gly or Pro eliminates the targeted side chain beyond C␤ and disrupts any interaction that involves that side chain, without introducing new interactions and with the lowest probability of altering the conformation of the polypeptide backbone (5,6). A few groups have applied this approach for a systematic thermodynamic dissection of interfaces in dimeric heterocomplexes (7)(8)(9)(10)(11)(12)(13)(14)(15)(16) or small homo-oligomers (17)(18)(19)(20)(21). These studies have substantially advanced the molecular understanding of protein-protein recognition.…”
mentioning
confidence: 99%
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“…Moreover, the critical CE(S/T)XD motif required for catalysis is provided by the adjacent subunit in the dimeric complex. Dimerization has also been shown to be critical for other family members of the PLP-dependent decarboxylases, such as eukaryotic ornithine decarboxylase, where the active site is completed by the contribution of Lys 69 and Cys 360 from opposing subunits (10,37). These are equivalent to the DAPDC Lys and Cys residues in the respective (Y/F)AXKA and CE(S/T)XD motifs.…”
Section: Discussionmentioning
confidence: 99%
“…46 -49). Indeed, we have previously demonstrated that ODC amino acid residues in the dimer interface that are distant from the active site are important for enzyme activity (44).…”
Section: Discussionmentioning
confidence: 99%