Authors: Daniel P. Dowling, Yan Kung, Anna K. Croft, Koli Taghizadeh, Wendy L. Kelly, Christopher T. Walsh, Catherine L. Drennan
Proceedings of the National Academy of Sciences 2016, 201608615.
Abstract: Here we investigate the structural basis for cyclization activity in hybrid polyketide synthase-nonribosomal peptide synthetases. This first structure of a cyclization (Cy) domain reveals an unexpected location for the enzyme active site, providing a fresh perspective on past mutational studies. Our structures also depict two 20-Å-long channels that create routes for the two tethered substrates to simultaneously reach the buried active site, affording substrate condensation and cyclization. Along with the Cy domain, these structures contain a covalently attached docking domain, providing insight into how protein modules work together to achieve uni-directionality in the biosynthesis of natural products.