期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 215, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2020.111319
关键词
1,10-phenanthroline; Thermolysin; Metalloprotease; Inhibitor; Metal chelation; Crystal structure
资金
- National Research Foundation of Korea [NRF-2017R1D1A1B03033087, NRF-2017M3A9F6029736]
The study aimed to understand the structural basis of zinc metalloproteinase inhibition by 1,10-phenanthroline through X-ray crystallography, revealing interactions between 1,10-phenanthroline and amino acids, as well as metal ions, in the proteinase.
Metalloproteases and their inhibitors are important in numerous fundamental biochemical phenomena and medical applications. The heterocyclic organic compound, 1,10-phenanthroline, forms a complex with transition metal ions and is a Zn2+-chelating metalloprotease inhibitor; however, the mechanism of 1,10-phenanthroline-based chelation inhibition has not been fully elucidated. This study aimed to understand the structural basis of zinc metalloproteinase inhibition by 1,10-phenanthroline. Herein, the crystal structure of thermolysin was determined in the absence and presence of 1,10-phenanthroline at 1.5 and 1.8 angstrom, respectively. In native thermolysin, Zn2+ at the active site is tetrahedrally coordinated by His142, His146, Glu166, and water molecule and contains three Ca2+ ions, which are involved in thermostability. In the crystal structure of 1,10-phenanthroline-treated thermolysin crystal, seven 1,10-phenanthroline molecules were observed on the surface of thermolysin. These molecules are stabilized by pi-pi stacking interactions with aromatic amino acids (Phe63, Tyr66, Tyr110, His216, and Try251) or between the 1,10-phenanthrolines. Moreover, interactions with Ser5 and Arg101 were also observed. In this structure, Zn2+ at the active site was completely chelated, but no large conformational changes were observed in Zn2+ coordination with amino acid residues. Ca2+ at the Ca3 site exposed to the solvent was chelated by 1,10-phenanthroline, resulting in a conformational change in the side chain of Asp56 and Gln61. Based on the surface structure, for 1,10-phenanthroline to chelate a metal, it is important that the metal is exposed on the protein surface and that there is no steric hindrance impairing 1,10-phenanthroline access by the amino acids around the metal.
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