Structural Basis for Phosphopantetheinyl Carrier Domain Interactions in the Terminal Module of Nonribosomal Peptide Synthetases Ye Liu, Tengfei Zheng,

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Structural Basis for Phosphopantetheinyl Carrier Domain Interactions in the Terminal Module of Nonribosomal Peptide Synthetases Ye Liu, Tengfei Zheng, Steven D. Bruner Chemistry & Biology Volume 18, Issue 11, Pages 1482-1488 (November 2011) DOI: 10.1016/j.chembiol.2011.09.018 Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 1 Strategy to Constrain Carrier Domain Interactions in NRPSs (A) Chemical structure of the phosphopantetheine substrate of terminal thioesterase (TE) domains in NRPSs, the peptide product is removed the peptide product from the NRPS assembly through nucleophilic hydrolysis or cyclization. (B) General approach to target specific enzyme active sites using a designed coenzyme A (CoA) analog loaded on to carrier domain (PCP) with a phosphopantetheinyl transferase (PPTase). (C) Targeting thioesterase domains with electrophile-based phosphopantetheine analogs. After conjugation to a PCP domain with PPTase, α-chloroacetyl-amino-coenzyme A is a stable mimic of the natural thioester substrate and the α-Cl-amide functionality targets the active site. Chemistry & Biology 2011 18, 1482-1488DOI: (10.1016/j.chembiol.2011.09.018) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 2 The Overall Structure of the PCP-TE Conjugate (A) Ribbon representation of the protein dimer observed in the asymmetric unit. The PCP domain (orange) is connected to the TE domain (blue) through a short linker (red). The conjugated CoA analog is shown in licorice representation. Regions not observed in the electron density maps are indicated by dashed lines. (B) Closeup view of one of the monomer didomains. See also Figures S1 and S2. Chemistry & Biology 2011 18, 1482-1488DOI: (10.1016/j.chembiol.2011.09.018) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 3 The Structure of the ppant Arm and Interactions with the TE Domain Key residues are shown in licorice format (A) and graphical representation (B). (C) A sigma-weighted composite omit electron density map (blue, contoured at 1.5σ) along with an Fo-Fc map (2.2σ) computed without the ppant arm. Chemistry & Biology 2011 18, 1482-1488DOI: (10.1016/j.chembiol.2011.09.018) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 4 Domain-Domain Interactions The interdomain contacts between the PCP domain (orange) and the TE domain are highlighted. The two distinct regions of the TE domain are designated: lid (light blue) and the α,β fold (dark blue). See also Figure S4. Chemistry & Biology 2011 18, 1482-1488DOI: (10.1016/j.chembiol.2011.09.018) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 5 Interaction of the ppant Arm with the Active Site Of the TE Domain (A) Residues of the catalytic triad (Ser1138, His1271, Asp1165) and oxyanion hole (Ala1074 and Leu1139) are shown in licorice representation. (B) Proposed mechanism for fate of the α-Cl-amide moiety in the active site. See also Figures S5 and S6. Chemistry & Biology 2011 18, 1482-1488DOI: (10.1016/j.chembiol.2011.09.018) Copyright © 2011 Elsevier Ltd Terms and Conditions