Fundamental processes in living systems, including growth, sensation, metabolism, and even disease, are often defined by the way a protein interacts with an atom, ion, or small molecule. Protein tyrosine phosphatase (PTP) enzymes are involved in a wide range of signaling pathways and cellular processes that are regulated by the reversible phosphorylation of tyrosine residues. For example, protein tyrosine phosphatase 1B (PTP1B) is involved in regulating the insulin and leptin signaling pathways, and therefore provides a promising therapeutic target for treating diabetes and obesity. However, the challenge remains to find small molecule ligands with high enough selectivity toward PTP1B to serve as potential drug candidates.<br/>In this work, we used molecular dynamics simulations, validated by experimental NMR measurements, to determine the binding sites of small molecule inhibitors for PTP1B. In particular, we investigated the inhibition mechanism for the non-competitive inhibitor, chlorogenic acid. Our findings provide insight into the relation between the ligand binding site location and the inhibition of various steps in the PTP1B mechanism.

Mechanisms for allosteric inhibition of protein tyrosine phosphatase 1B

253rd National Meeting (2017)

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