期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 28, 页码 11308-11313出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206710110
关键词
enzyme catalysis; general-base catalysis; noncovalent interactions
资金
- National Science Foundation [MCB-1121778]
- National Institutes of Health (NIH)
- Department of Energy, Office of Biological and Environmental Research
- NIH, National Center for Research Resources (NCRR), Biomedical Technology Program
- National Institute of General Medical Sciences
- NCRR, a component of the NIH [5 P41 RR001209]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1121778] Funding Source: National Science Foundation
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.
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