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Related Experiment Video

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Measuring Enzymatic Stability by Isothermal Titration Calorimetry

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Published on: March 26, 2019

Protein Stability Effects in Aggregate-Based Enzyme Inhibition.

Hayarpi Torosyan¹, Brian K Shoichet¹

¹Department of Pharmaceutical Chemistry , University of California, San Francisco , 1700 Fourth Street , San Francisco , California 94143-2550 , United States.

Journal of Medicinal Chemistry

|October 8, 2019

Summary

Small-molecule aggregates inhibit proteins, with less stable proteins being more susceptible. This finding impacts drug discovery by explaining artifact variability due to protein concentration and stability.

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Area of Science:

Biochemistry
Chemical Biology
Drug Discovery

Background:

Small-molecule aggregates cause artifacts in early drug discovery.
Protein susceptibility to aggregate inhibition is not well understood.
Potential reasons include protein concentration sensitivity and protein unfolding.

Purpose of the Study:

To investigate the role of protein stability in aggregate-based inhibition.
To differentiate between concentration-dependent and stability-dependent inhibition.
To understand the selectivity of small-molecule aggregate inhibition.

Main Methods:

Utilized differentially stable point mutants of TEM-1 β-lactamase.
Assessed protein aggregate binding affinity.
Measured inhibition potency across varying protein stabilities.

Main Results:

Destabilized TEM-1 β-lactamase mutants showed higher affinity for aggregates and were more potently inhibited.
Moxalactam destabilized some mutants, increasing their binding to colloidal particles.
A stabilized mutant exhibited weaker binding to aggregates.

Conclusions:

Less stable enzymes are more readily sequestered and inhibited by colloidal aggregates.
Protein stability is a key determinant of susceptibility to aggregate-based inhibition.
Findings provide insights into drug discovery artifacts and protein-aggregate interactions.