A carrier protein strategy yields the structure of dalbavancin.

Journal of the American Chemical Society
Nicoleta J EconomouPatrick J Loll

Abstract

Many large natural product antibiotics act by specifically binding and sequestering target molecules found on bacterial cells. We have developed a new strategy to expedite the structural analysis of such antibiotic-target complexes, in which we covalently link the target molecules to carrier proteins, and then crystallize the entire carrier-target-antibiotic complex. Using native chemical ligation, we have linked the Lys-D-Ala-D-Ala binding epitope for glycopeptide antibiotics to three different carrier proteins. We show that recognition of this peptide by multiple antibiotics is not compromised by the presence of the carrier protein partner, and use this approach to determine the first-ever crystal structure for the new therapeutic dalbavancin. We also report the first crystal structure of an asymmetric ristocetin antibiotic dimer, as well as the structure of vancomycin bound to a carrier-target fusion. The dalbavancin structure reveals an antibiotic molecule that has closed around its binding partner; it also suggests mechanisms by which the drug can enhance its half-life by binding to serum proteins, and be targeted to bacterial membranes. Notably, the carrier protein approach is not limited to peptide ligands such as Lys-D-...Continue Reading

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Citations

Jul 4, 2012·Proceedings of the National Academy of Sciences of the United States of America·Rong ShiMiroslaw Cygler
Mar 23, 2013·Acta Crystallographica. Section D, Biological Crystallography·Nicoleta J EconomouPatrick J Loll
Mar 13, 2014·Organic & Biomolecular Chemistry·Mu ChengMatthew A Cooper
Oct 18, 2012·Chemical Communications : Chem Comm·Jean-Christophe M Monbaliu, Alan R Katritzky
May 9, 2014·Chemistry : a European Journal·Juan TreviñoMaría J Hernáiz
Oct 8, 2014·Acta Crystallographica. Section F, Structural Biology Communications·Patrick J LollScott L Melideo
Jul 7, 2015·Acta Crystallographica. Section F, Structural Biology Communications·Bostjan KobeSimon J Williams
Aug 5, 2015·Expert Opinion on Pharmacotherapy·Sheena Ramdeen, Helen W Boucher
Jan 15, 2020·Antimicrobial Agents and Chemotherapy·Oriana SimonettiOscar Cirioni
May 23, 2013·Journal of the American Chemical Society·Tejas P Pathak, Scott J Miller
Mar 6, 2015·Journal of the American Chemical Society·Walter J WeverAlbert A Bowers
Jan 25, 2018·ACS Infectious Diseases·Mark A T BlaskovichMatthew A Cooper
Jun 6, 2017·Chemical Reviews·Christopher R Shugrue, Scott J Miller
Nov 20, 2021·Medicinal Research Reviews·Vladimir VimbergGabriela B Novotná

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