Multienzyme docking in hybrid megasynthetases.
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 beta-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 beta-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. c.d.richter.03@cantab.net
Carsten D
CD
Richter
Daniel
D
Nietlispach
R William
RW
Broadhurst
Kira J
KJ
Weissman
D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D001665:Binding Sites; D005818:Genetic Engineering; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D009231:Myxococcales / Q000201:enzymology*; D010453:Peptide Synthases / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D048630:Polyketide Synthases / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics
D001426:Bacterial Proteins; D009097:Multienzyme Complexes; D048630:Polyketide Synthases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase