Mapping the catalytic conformations of an assembly-line polyketide synthase module

Cogan, Dillon P.; Zhang, Kaiming; Li, Xiuyuan; Li, Shanshan; Pintilie, Grigore D.; Roh, Soung-Hun; Craik, Charles S.; Chiu, Wah; Khosla, Chaitan

doi:10.1126/science.abi8358

Title: Mapping the catalytic conformations of an assembly-line polyketide synthase module

Journal Article · Fri Nov 05 00:00:00 UTC 2021 · Science

DOI: https://doi.org/10.1126/science.abi8358 · OSTI ID:1870422

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Stanford Univ., CA (United States)
Stanford Univ., CA (United States); Univ. of Science and Technology of China, Hefei (China). MOE Key Laboratory for Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale
Stanford Univ., CA (United States); Seoul National Univ. (South Korea). Institute of Molecular Biology & Genetics
Univ. of California, San Francisco, CA (United States)
Stanford Univ., CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Assembly-line polyketide synthases, such as the 6-deoxyerythronolide B synthase (DEBS), are large enzyme factories prized for their ability to produce specific and complex polyketide products. By channeling protein-tethered substrates across multiple active sites in a defined linear sequence, these enzymes facilitate programmed small-molecule syntheses that could theoretically be harnessed to access countless polyketide product structures. Additionally, using cryogenic electron microscopy to study DEBS module 1, we present a structural model describing this substrate-channeling phenomenon. Our 3.2- to 4.3-angstrom-resolution structures of the intact module reveal key domain-domain interfaces and highlight an unexpected module asymmetry. We also present the structure of a product-bound module that shines light on a recently described “turnstile” mechanism for transient gating of active sites along the assembly line.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1870422

Journal Information:: Science, Journal Name: Science Journal Issue: 6568 Vol. 374; ISSN 0036-8075

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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