4I40

crystal structure of Staphylococcal inositol monophosphatase-1: 50mM LiCl inhibited complex

Summary for 4I40

• Entry DOI: 10.2210/pdb4i40/pdb
• Related: 3QMF 3RYD 4G61 4I3Y 4PTK
• Descriptor: Inositol monophosphatase family protein, MAGNESIUM ION, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: inositol monophosphatase-1, li inhibition, magnesium binding, cytoplasmic, hydrolase
• Biological source: Staphylococcus aureus subsp. aureus
• Total number of polymer chains: 2
• Total formula weight: 63315.87

Authors

Dutta, A.,Bhattacharyya, S.,Dutta, D.,Das, A.K. (deposition date: 2012-11-27, release date: 2013-11-27, Last modification date: 2023-11-08)

Primary citation

Dutta, A.,Bhattacharyya, S.,Dutta, D.,Das, A.K.
Structural elucidation of the binding site and mode of inhibition of Li(+) and Mg(2+) in inositol monophosphatase.
Febs J., 281:5309-5324, 2014

PubMed Abstract: Mg(2+) -dependent, Li(+) -sensitive phosphatases are a widely distributed family of enzymes with significant importance throughout the biological kingdom. Inositol monophosphatase (IMPase) is an important target of Li(+) -based therapeutic agents in manic depressive disorders. However, despite decades of intense research efforts, the precise mechanism of Li(+) -induced inhibition of IMPase remains obscured. Here we describe a structural investigation of the Li(+) binding site in staphylococcal IMPase I (SaIMPase I) using X-ray crystallography. The biochemical study indicated common or overlapping binding sites for Mg(2+) and Li(+) in the active site of SaIMPase I. The crystal structure of the SaIMPase I ternary product complex shows the presence of a phosphate and three Mg(2+) ions (namely Mg1, Mg2 and Mg3) in the active site. As Li(+) is virtually invisible in X-ray crystallography, competitive displacement of Mg(2+) ions from the SaIMPase I ternary product complex as a function of increasing LiCl concentration was used to identify the Li(+) binding site. In this approach, the disappearing electron density of Mg(2+) ions due to Li(+) ion binding was traced, and the Mg(2+) ion present at the Mg2 binding site was found to be replaced. Moreover, based on a detailed comparative investigation of the phosphate orientation and coordination states of Mg(2+) binding sites in enzyme-substrate and enzyme-product complexes, inhibition mechanisms for Li(+) and Mg(2+) are proposed.

PubMed: 25263816
DOI: 10.1111/febs.13070

Experimental method

X-RAY DIFFRACTION (2.5 Å)