Article abstract
Nature Chemical Biology 4, 75 - 81 (2008)
Published online: 9 December 2007 | doi:10.1038/nchembio.2007.61
Multienzyme docking in hybrid megasynthetases
Carsten D Richter1,2, Daniel Nietlispach1, R William Broadhurst1 & Kira J Weissman1,2
Abstract
Hybrid multienzyme systems composed of polyketide synthase (PKS) and nonribosomal polypeptide synthetase (NRPS) modules direct the biosynthesis of clinically valuable natural products in bacteria. The fidelity of this process depends on specific recognition between successive polypeptides in each assembly line—interactions that are mediated by terminal 'docking domains'. We have identified a new family of N-terminal docking domains, exemplified by TubCdd from the tubulysin system of Angiococcus disciformis An d48. TubCdd is homodimeric, which suggests that NRPS subunits in mixed systems self-associate to interact with partner PKS homodimers. The NMR structure of TubCdd reveals a new fold featuring an exposed 
-hairpin that serves as the binding site for the C-terminal docking domain of the partner polypeptide. The pattern of charged residues on the contact surface of the -hairpin is a key determinant of the interaction and seems to constitute a 'docking code' that can be used to alter binding affinity.
- Department of Biochemistry, 80 Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, UK.
- Present addresses: Bohmann & Loosen, Anwaltssozietät, Nymphenburger Strasse 1, 80335 Munich, Germany (C.D.R.) and Pharmaceutical Biotechnology, Saarland University, Im Stadtwald, 66123 Saarbrücken, Germany (K.J.W.).
Correspondence to: Carsten D Richter1,2 e-mail: c.d.richter.03@cantab.net
Correspondence to: R William Broadhurst1 e-mail: r.w.broadhurst@bioc.cam.ac.uk
Correspondence to: Kira J Weissman1,2 e-mail: k.weissman@mx.uni-saarland.de
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