title: Visualization of a substrate-induced productive conformation of the catalytic triad of the Neisseria meningitidis peptidoglycan O-acetylesterase reveals mechanistic conservation in SGNH esterase family members.
abstract: Peptidoglycan O-acetylesterase (Ape1), which is required for host survival in Neisseria sp., belongs to the diverse SGNH hydrolase superfamily, which includes important viral and bacterial virulence factors. Here, multi-domain crystal structures of Ape1 with an SGNH catalytic domain and a newly identified putative peptidoglycan-detection module are reported. Enzyme catalysis was performed in Ape1 crystals and key catalytic intermediates along the SGNH esterase hydrolysis reaction pathway were visualized, revealing a substrate-induced productive conformation of the catalytic triad, a mechanistic detail that has not previously been observed. This substrate-induced productive conformation of the catalytic triad shifts the established dogma on these enzymes, generating valuable insight into the structure-based design of drugs targeting the SGNH esterase superfamily.
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France.
authors.forename: Allison H
authors.initials: AH
authors.lastname: Williams
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France.
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Veyrier
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bonis
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Michaud
authors.affiliation: Institut Pasteur, CNRS-UMR3528, Plateforme de Biophysique, 25 Rue du Dr. Roux, 75724 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Raynal
authors.affiliation: Institut Pasteur, Unité Infection Bactériennes Invasives, Dept. Infection et Epidémiologie, 28 Rue du Dr. Roux, 75015 Paris, France.
authors.forename: Muhamed Kheir
authors.initials: MK
authors.lastname: Taha
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: White
authors.affiliation: Institut Pasteur, CNRS-UMR3528, Plateforme de Cristallographie, 25 Rue du Dr. Roux, 75724 Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Haouz
authors.affiliation: Institut Pasteur, Unité Biologie et génétique de la paroi bactérienne, Dept. Microbiologie, 28 Rue du Dr. Roux, 75015 Paris, France.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Boneca
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004950:Esterases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D009345:Neisseria meningitidis / Q000737:chemistry*; D010457:Peptidoglycan / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D001426:Bacterial Proteins; D010457:Peptidoglycan; D004950:Esterases
keywords: Ape1; SGNH hydrolase superfamily; peptidoglycan O-acetylesterase