A gratuitous β-Lactamase inducer uncovers hidden active site dynamics of the Staphylococcus aureus BlaR1 sensor domain

PloS One
Thomas E Frederick, Jeffrey W Peng

Abstract

Increasing evidence shows that active sites of proteins have non-trivial conformational dynamics. These dynamics include active site residues sampling different local conformations that allow for multiple, and possibly novel, inhibitor binding poses. Yet, active site dynamics garner only marginal attention in most inhibitor design efforts and exert little influence on synthesis strategies. This is partly because synthesis requires a level of atomic structural detail that is frequently missing in current characterizations of conformational dynamics. In particular, while the identity of the mobile protein residues may be clear, the specific conformations they sample remain obscure. Here, we show how an appropriate choice of ligand can significantly sharpen our abilities to describe the interconverting binding poses (conformations) of protein active sites. Specifically, we show how 2-(2'-carboxyphenyl)-benzoyl-6-aminopenicillanic acid (CBAP) exposes otherwise hidden dynamics of a protein active site that binds β-lactam antibiotics. When CBAP acylates (binds) the active site serine of the β-lactam sensor domain of BlaR1 (BlaRS), it shifts the time scale of the active site dynamics to the slow exchange regime. Slow exchange enables ...Continue Reading

References

Dec 1, 1968·Journal of Bacteriology·J Leggate, W H Holms
Oct 1, 1994·Trends in Microbiology·G L Archer, D M Niemeyer
Oct 1, 1993·Protein Science : a Publication of the Protein Society·A W ChanJ M Thornton
May 1, 1993·Antimicrobial Agents and Chemotherapy·C J Hackbarth, H F Chambers
Oct 1, 1995·Clinical Microbiology Reviews·D M Livermore
Nov 13, 1998·Proceedings of the National Academy of Sciences of the United States of America·M SalzmannK Wüthrich
Mar 14, 2001·Science·G L Archer, J M Bosilevac
Jul 20, 2001·Methods in Enzymology·D S Wishart, D A Case
Nov 17, 2001·Chemical Reviews·J A Gomes, R B Mallion
Jul 3, 2003·Nature Reviews. Drug Discovery·Simon J Teague
Aug 24, 2004·The Journal of Biological Chemistry·Mark S WilkeNatalie C J Strynadka
Apr 12, 2005·BMC Infectious Diseases·Matthew E FalagasArgyris Michalopoulos
Sep 7, 2005·Cellular and Molecular Life Sciences : CMLS·C C S FudaS Mobashery
Jul 4, 2006·Proceedings of the National Academy of Sciences of the United States of America·Kanjana ThumanuChristopher Wharton
Mar 9, 2007·Journal of the American Chemical Society·Jooyoung Cha, Shahriar Mobashery
Oct 18, 2007·JAMA : the Journal of the American Medical Association·R Monina KlevensUNKNOWN Active Bacterial Core surveillance (ABCs) MRSA Investigators
Aug 29, 2009·Science·Michael A Fischbach, Christopher T Walsh
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·David D BoehrPeter E Wright
Aug 25, 2010·Journal of Biomolecular NMR·Julianne L Kitevski-LeBlancR Scott Prosser
Aug 24, 2011·Nature Chemistry·Patrick R ConnellyMark A Murcko
Oct 22, 2011·Journal of Magnetic Resonance·Kang Chen, Nico Tjandra
Nov 2, 2011·Proceedings of the National Academy of Sciences of the United States of America·Filomena De LucaJean-Denis Docquier
May 10, 2013·Annual Review of Biophysics·John D Chodera, David L Mobley
Mar 25, 2014·Journal of Magnetic Resonance·Arthur G Palmer
Dec 2, 2014·Nature Reviews. Microbiology·Jessica M A BlairLaura J V Piddock
Dec 29, 2015·Journal of Molecular Biology·Lewis E Kay
Mar 10, 2016·Progress in Nuclear Magnetic Resonance Spectroscopy·George P Lisi, J Patrick Loria

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Citations

Nov 21, 2019·Protein Science : a Publication of the Protein Society·Jed F Fisher, Shahriar Mobashery
Dec 25, 2019·Antimicrobial Agents and Chemotherapy·Wouter ElingsMarcellus Ubbink
Dec 30, 2020·Chemical Reviews·Jed F Fisher, Shahriar Mobashery
Jul 17, 2021·Journal of Molecular Biology·Jamie VanPeltJeffrey W Peng

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Methods Mentioned

BETA
acylation
phage-display
X-ray
circular dichroism
NMR
chemical exchange
deacylation

Software Mentioned

TIFF
CARA
SPARKY

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