Functional dichotomy in the 16S rRNA (m1 A1408) methyltransferase family and control of catalytic activity via a novel tryptophan mediated loop reorganization

Witek, Marta A.; Conn, Graeme L.

doi:10.1093/nar/gkv1306

Title: Functional dichotomy in the 16S rRNA (m¹ A1408) methyltransferase family and control of catalytic activity via a novel tryptophan mediated loop reorganization

Journal Article · 23 November 2015 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gkv1306 · OSTI ID:1237755

Witek, Marta A. ^[1];

^[1]

Emory Univ. School of Medicine, Atlanta, GA (United States)

Methylation of the bacterial small ribosomal subunit (16S) rRNA on the N1 position of A1408 confers exceptionally high-level resistance to a broad spectrum of aminoglycoside antibiotics. Here, we present a detailed structural and functional analysis of the Catenulisporales acidiphilia 16S rRNA (m¹A1408) methyltransferase (‘CacKam’). The apo CacKam structure closely resembles other m1A1408 methyltransferases within its conserved SAM-binding fold but the region linking core β strands 6 and 7 (the ‘β6/7 linker’) has a unique, extended structure that partially occludes the putative 16S rRNA binding surface, and sequesters the conserved and functionally critical W203 outside of the CacKam active site. Substitution of conserved residues in the SAM binding pocket reveals a functional dichotomy in the 16S rRNA (m¹A1408) methyltransferase family, with two apparently distinct molecular mechanisms coupling cosubstrate/ substrate binding to catalytic activity. Our results additionally suggest that CacKam exploits the W203-mediated remodeling of the β6/7 linker as a novel mechanism to control 30S substrate recognition and enzymatic turnover.

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

Sponsoring Organization:: National Inst. of Health-National Inst. of Allergy and Infectious Diseases; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1237755

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 1 Vol. 44; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Molecular and Enzymatic Profiles of Mammalian DNA Methyltransferases: Structures and Targets for Drugs Xu, F.; Mao, C.; Ding, Y. Current Medicinal Chemistry, Vol. 17, Issue 33 https://doi.org/10.2174/092986710793205372	journal	November 2012

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Title: Functional dichotomy in the 16S rRNA (m¹ A1408) methyltransferase family and control of catalytic activity via a novel tryptophan mediated loop reorganization