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Allosteric regulation of protease activity by small molecules.

ABSTRACT: Proteases regulate a plethora of biological processes. Because they irreversibly cleave peptide bonds, the activity of proteases is strictly controlled. While there are many ways to regulate protease activity, an emergent mechanism is the modulation of protease function by small molecules acting at allosteric sites. This mode of regulation holds the potential to allow for the specific and temporal control of a given biological process using small molecules. These compounds also serve as useful tools for studying protein dynamics and function. This review highlights recent advances in identifying and characterizing natural and synthetic small molecule allosteric regulators of proteases and discusses their utility in studies of protease function, drug discovery and protein engineering.

SUBMITTER: Shen A

PROVIDER: S-EPMC4356121 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Allosteric regulation of protease activity by small molecules.

Shen Aimee A

Molecular bioSystems 20100610 8

Proteases regulate a plethora of biological processes. Because they irreversibly cleave peptide bonds, the activity of proteases is strictly controlled. While there are many ways to regulate protease activity, an emergent mechanism is the modulation of protease function by small molecules acting at allosteric sites. This mode of regulation holds the potential to allow for the specific and temporal control of a given biological process using small molecules. These compounds also serve as useful t ...[more]

PMID: 20539873

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Project description:Glutamate dehydrogenase (GDH) is a key enzyme interlinking carbon and nitrogen metabolism. Recent discoveries of the GDH specific role in breast cancer, hyperinsulinism/hyperammonemia (HI/HA) syndrome, and neurodegenerative diseases have reinvigorated interest on GDH regulation, which remains poorly understood despite extensive and long standing studies. Notwithstanding the growing evidence of the complexity of allosteric network behind GDH regulation, identifications of allosteric factors and associated mechanisms are paramount to deepen our understanding of the complex dynamics that regulate GDH enzymatic activity. Combining structural analyses of cryo-electron microscopy data with molecular dynamic simulations, here we show that the cofactor NADH is a key player in the GDH regulation process. Our structural analysis indicates that, binding to the regulatory sites in proximity of the antenna region, NADH acts as a positive allosteric modulator by enhancing both the affinity of the inhibitor GTP binding and inhibition of GDH catalytic activity. We further show that the binding of GTP to the NADH-bound GDH activates a triangular allosteric network, interlinking the inhibitor with regulatory and catalytic sites. This allostery produces a local conformational rearrangement that triggers an anticlockwise rotational motion of interlinked alpha-helices with specific tilted helical extension. This structural transition is a fundamental switch in the GDH enzymatic activity. It introduces a torsional stress, and the associated rotational shift in the Rossmann fold closes the catalytic cleft with consequent inhibition of the deamination process. In silico mutagenesis examinations further underpin the molecular basis of HI/HA dominant mutations and consequent over-activity of GDH through alteration of this allosteric communication network. These results shed new light on GDH regulation and may lay new foundation in the design of allosteric agents.

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Allosteric regulation of protease activity by small molecules.

Publications

Allosteric regulation of protease activity by small molecules.

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