Molecular basis for the broad substrate selectivity of a peptide prenyltransferase

Hao, Yue; Pierce, Elizabeth; Roe, Daniel; Morita, Maho; McIntosh, John A.; Agarwal, Vinayak; Cheatham, III, Thomas E.; Schmidt, Eric W.; Nair, Satish K.

doi:10.1073/pnas.1609869113

Title: Molecular basis for the broad substrate selectivity of a peptide prenyltransferase

Journal Article · Mon Nov 21 00:00:00 EST 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1609869113· OSTI ID:1335987

Hao, Yue ^[1]; Pierce, Elizabeth ^[2]; Roe, Daniel ^[2]; Morita, Maho ^[2]; McIntosh, John A. ^[2]; Agarwal, Vinayak ^[1]; Cheatham, III, Thomas E. ^[2]; Schmidt, Eric W. ^[2]; Nair, Satish K. ^[1]

Univ. of Illinois at Urbana-Champaign, Urbana, IL (United States)
Univ. of Utah, Salt Lake City, UT (United States)

The cyanobactin prenyltransferases catalyze a series of known or unprecedented reactions on millions of different substrates, with no easily observable recognition motif and exquisite regioselectivity. Here we define the basis of broad substrate tolerance for the otherwise uncharacterized TruF family. We determined the structures of the Tyr-prenylating enzyme PagF, in complex with an isoprenoid donor analog and a panel of linear and macrocyclic peptide substrates. Unexpectedly, the structures reveal a truncated barrel fold, wherein binding of large peptide substrates is necessary to complete a solvent-exposed hydrophobic pocket to form the catalytically competent active site. Kinetic, mutational, chemical, and computational analyses revealed the structural basis of selectivity, showing a small motif within peptide substrates that is sufficient for recognition by the enzyme. Attaching this 2-residue motif to two random peptides results in their isoprenylation by PagF, demonstrating utility as a general biocatalytic platform for modifications on any peptide substrate.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: GM102602; GM103219

OSTI ID:: 1335987

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 49; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 37 works

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Molecular Insight into the Mg ²⁺ -Dependent Allosteric Control of Indole Prenylation by Aromatic Prenyltransferase AmbP1 Awakawa, Takayoshi; Mori, Takahiro; Nakashima, Yu Angewandte Chemie International Edition, Vol. 57, Issue 23 https://doi.org/10.1002/anie.201800855	journal	May 2018
Parallel lives of symbionts and hosts: chemical mutualism in marine animals Morita, Maho; Schmidt, Eric W. Natural Product Reports, Vol. 35, Issue 4 https://doi.org/10.1039/c7np00053g	journal	January 2018

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59 BASIC BIOLOGICAL SCIENCES
RiPP
biosynthesis
prenylation
crystallography

Title: Molecular basis for the broad substrate selectivity of a peptide prenyltransferase

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