8TPW

Crosslinked 6-deoxyerythronolide B synthase (DEBS) Module 3 in complex with antibody fragment 1B2: cis-oriented 1B2 and ACP

Summary for 8TPW

• Entry DOI: 10.2210/pdb8tpw/pdb
• EMDB information: 41495 41496
• Descriptor: EryAII,EryAII,EryAII,EryAII,6-deoxyerythronolide-B synthase EryA3, modules 5 and 6, Antibody Fragment 1B2, Heavy Chain, Antibody Fragment 1B2, Light Chain (3 entities in total)
• Functional Keywords: polyketide synthase, antibody, biosynthetic protein
• Biological source: Saccharopolyspora erythraea; More
• Total number of polymer chains: 5
• Total formula weight: 611632.18

Authors

Cogan, D.P.,Soohoo, A.M.,Chen, M.,Brodsky, K.L.,Liu, Y.,Khosla, C. (deposition date: 2023-08-05, release date: 2024-08-07, Last modification date: 2024-09-04)

Primary citation

Cogan, D.P.,Soohoo, A.M.,Chen, M.,Liu, Y.,Brodsky, K.L.,Khosla, C.
Structural basis for intermodular communication in assembly-line polyketide biosynthesis.
Nat.Chem.Biol., 2024

PubMed Abstract: Assembly-line polyketide synthases (PKSs) are modular multi-enzyme systems with considerable potential for genetic reprogramming. Understanding how they selectively transport biosynthetic intermediates along a defined sequence of active sites could be harnessed to rationally alter PKS product structures. To investigate functional interactions between PKS catalytic and substrate acyl carrier protein (ACP) domains, we employed a bifunctional reagent to crosslink transient domain-domain interfaces of a prototypical assembly line, the 6-deoxyerythronolide B synthase, and resolved their structures by single-particle cryogenic electron microscopy (cryo-EM). Together with statistical per-particle image analysis of cryo-EM data, we uncovered interactions between ketosynthase (KS) and ACP domains that discriminate between intra-modular and inter-modular communication while reinforcing the relevance of conformational asymmetry during the catalytic cycle. Our findings provide a foundation for the structure-based design of hybrid PKSs comprising biosynthetic modules from different naturally occurring assembly lines.

PubMed: 39179672
DOI: 10.1038/s41589-024-01709-y

Experimental method

ELECTRON MICROSCOPY (3.46 Å)