Compound Molecular Logic in Accessing the Active Site of Mycobacterium tuberculosis Protein Tyrosine Phosphatase B

Thomas E. Morrell, Ilona U. Rafalska-Metcalf, Haw Yang*, Jhih-Wei Chu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Protein tyrosine phosphatase B (PtpB) from Mycobacterium tuberculosis (Mtb) extends the bacteria's survival in hosts and hence is a potential target for Mtb-specific drugs. To study how Mtb-specific sequence insertions in PtpB may regulate access to its active site through large-amplitude conformational changes, we performed free-energy calculations using an all-atom explicit solvent model. Corroborated by biochemical assays, the results show that PtpB's active site is controlled via an "either/or" compound conformational gating mechanism, an unexpected discovery that Mtb has evolved to bestow a single enzyme with such intricate logical operations. In addition to providing unprecedented insights for its active-site surroundings, the findings also suggest new ways of inactivating PtpB.

Original languageEnglish
Pages (from-to)14747-14752
Number of pages6
JournalJournal of the American Chemical Society
Volume140
Issue number44
DOIs
StatePublished - 7 Nov 2018

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