Conformational freedom in tight binding enzymatic transition-state analogues

Matthew W. Motley, Vern L. Schramm, Steven D. Schwartz

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Transition-state analogues of bacterial 5′-methylthioadenosine/S- adenosylhomocysteine nucleosidases (MTANs) disrupt quorum-sensing pathways in Escherichia coli and Vibrio cholerae, demonstrating the potential to limit pathogenicity without placing bacteria under intense selective pressure that leads to antibiotic resistance. Despite the similarity of the crystal structures of E. coli MTAN (EcMTAN) and V. cholerae MTAN (VcMTAN) bound to DADMe-Immucillin-A transition-state (TS) analogues, EcMTAN demonstrates femtomolar affinity for BuT-DADMe-Immucillin-A (BDIA) whereas VcMTAN possesses only picomolar affinity. Protein dynamic interactions are therefore implicated in this inhibitor affinity difference. We conducted molecular dynamics simulations of both EcMTAN and VcMTAN in complex with BDIA to explore differences in protein dynamic architecture. Simulations revealed that electrostatic and hydrophobic interactions with BDIA are similar for both enzymes and thus unlikely to account for the difference in inhibitor affinity. The EcMTAN-BDIA complex reveals a greater flexibility and conformational freedom of catalytically important atoms. We propose that conserved motions related to the EcMTAN transition state correlate with the increased affinity of BDIA for EcMTAN. Transition-state analogues permitting protein motion related to formation of the transition state are better mimics of the enzymatic transition state and can bind more tightly than those immobilizing catalytic site dynamics.

Original languageEnglish (US)
Pages (from-to)9591-9597
Number of pages7
JournalJournal of Physical Chemistry B
Volume117
Issue number33
DOIs
Publication statusPublished - Aug 22 2013

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ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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