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Use of anion--aromatic interactions to position the general base in the ketosteroid isomerase active site.(BIOCHEMISTRY)(Author abstract)

Schwans, Jason P. ; Sunden, Fanny ; Lassila, Jonathan K. ; Gonzalez, Ana ; Tsai, Yingssu ; Herschlag, Daniel

Proceedings of the National Academy of Sciences of the United States, July 9, 2013, Vol.110(28), p.11308(6) [Periódico revisado por pares]

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  • Título:
    Use of anion--aromatic interactions to position the general base in the ketosteroid isomerase active site.(BIOCHEMISTRY)(Author abstract)
  • Autor: Schwans, Jason P. ; Sunden, Fanny ; Lassila, Jonathan K. ; Gonzalez, Ana ; Tsai, Yingssu ; Herschlag, Daniel
  • Assuntos: Surface Active Agents -- Research ; Surface Active Agents -- Analysis ; Hydrogen -- Usage ; Hydrogen -- Research ; Hydrogen -- Analysis
  • É parte de: Proceedings of the National Academy of Sciences of the United States, July 9, 2013, Vol.110(28), p.11308(6)
  • Descrição: Although the cation--pi pair, formed between a side chain or substrate cation and the negative electrostatic potential of a pi system on the face of an aromatic ring, has been widely discussed and has been shown to be important in protein structure and protein--ligand interactions, there has been little discussion of the potential structural and functional importance in proteins of the related anion--aromatic pair (i.e., interaction of a negatively charged group with the positive electrostatic potential on the ring edge of an aromatic group). We posited, based on prior structural information, that anion--aromatic interactions between the anionic Asp general base and Phe54 and Phe116 might be used instead of a hydrogen-bond network to position the general base in the active site of ketosteroid isomerase from Comamonas testosteroni as there are no neighboring hydrogen-bonding groups. We have tested the role of the Phe residues using site-directed mutagenesis, double-mutant cycles, and high-resolution X-ray crystallography. These results indicate a catalytic role of these Phe residues. Extensive analysis of the Protein Data Bank provides strong support for a catalytic role of these and other Phe residues in providing anion--aromatic interactions that position anionic general bases within enzyme active sites. Our results further reveal a potential selective advantage of Phe in certain situations, relative to more traditional hydrogen-bonding groups, because it can simultaneously aid in the binding of hydrophobic substrates and positioning of a neighboring general base. enzyme catalysis | general-base catalysis | noncovalent interactions www.pnas.org/cgi/doi/ 10.1073/pnas.1206710110
  • Idioma: English

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