ORCID Profile
0000-0001-6744-5061
Current Organisations
Rosalind Franklin Institute
,
University of Oxford
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Publisher: The Royal Society
Date: 23-04-2018
Abstract: Hydroxamate groups play key roles in the biological function of erse natural products. Important ex les include trichostatin A, which inhibits histone deacetylases via coordination of the active site zinc(II) ion with a hydroxamate group, and the desferrioxamines, which use three hydroxamate groups to chelate ferric iron. Desferrioxamine biosynthesis in Streptomyces species involves the DesD-catalysed condensation of various N -acylated derivatives of N -hydroxycadaverine with two molecules of N -succinyl- N -hydroxycadaverine to form a range of linear and macrocyclic tris-hydroxamates. However, the mechanism for assembly of the various N -acyl- N -hydroxycadaverine substrates of DesD from N -hydroxycadaverine has until now been unclear. Here we show that the desC gene of Streptomyces coelicolor encodes the acyl transferase responsible for this process. DesC catalyses the N -acylation of N -hydroxycadaverine with acetyl, succinyl and myristoyl-CoA, accounting for the erse array of desferrioxamines produced by S. coelicolor . The X-ray crystal structure of DesE, the ferrioxamine lipoprotein receptor, in complex with ferrioxamine B (which is derived from two units of N -succinyl- N -hydroxycadaverine and one of N -acetyl- N -hydroxycadaverine) was also determined. This showed that the acetyl group of ferrioxamine B is solvent exposed, suggesting that the corresponding acyl group in longer chain congeners can protrude from the binding pocket, providing insights into their likely function. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology'. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-07-2022
Abstract: Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.
Publisher: International Union of Crystallography (IUCr)
Date: 31-10-2008
Publisher: International Union of Crystallography (IUCr)
Date: 09-1994
Publisher: Public Library of Science (PLoS)
Date: 30-08-2013
Publisher: Cold Spring Harbor Laboratory
Date: 23-07-2022
DOI: 10.1101/2022.07.21.500988
Abstract: The enzyme OphP is essential for the biosynthesis of the macrocyclic peptide omphalotin A, a dodecamer with 9 backbone N-methylations produced by the wood-degrading fungus Omphalotus olearius . Heterologous expression of OphP and the peptide-precursor protein OphMA in yeast, yields omphalotin A. Thus, Oph P was hypothesized to have a dual function catalyzing both endoproteolytic release of a peptide intermediate from OphMA, and macrocyclization of the multiply α-N-methylated core peptide with concomitant release of a C-terminal follower peptide. In our in vitro activity assays, OphP showed robust endoproteolytic and macrocyclase activity on α-N-methylated peptides but was unable to cleave OphMA. The enzyme had a strong preference for hydrophobic, highly α-N-methylated peptides and an α-N-methylated glycine residue at the P1 site. OphP adopts a canonical prolyl oligopeptidase (POP) fold with a predominantly hydrophobic substrate binding cleft, and a small and hydrophobic P1 binding pocket. We demonstrate that OphP is a POP-type macrocyclase with a specificity and a substrate route to the active site different from other members of the family. These results could be exploited for the biotechnological production of macrocyclic peptides with multiple backbone N-methylations, which are interesting due to their favorable pharmacological properties.
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1MB90044G
Publisher: Springer Science and Business Media LLC
Date: 24-04-2010
Publisher: Elsevier BV
Date: 12-2004
Publisher: International Union of Crystallography (IUCr)
Date: 11-1994
Publisher: Elsevier BV
Date: 09-2011
Publisher: International Union of Crystallography (IUCr)
Date: 11-1993
Publisher: Springer Science and Business Media LLC
Date: 02-2009
DOI: 10.1038/NCHEMBIO.145
Publisher: Elsevier BV
Date: 08-1993
Abstract: We have reproducibly crystallized recombinant trypanothione reductase from Trypanosoma cruzi. Yellow tetragonal crystals in the shape of elongated prisms have unit cell dimensions of a = 92.8 A, c = 156.6 A, Laue symmetry of 4/m and are suitable for a detailed structural analysis. Diffraction data to 2.7 A resolution have been recorded using synchrotron radiation at the Daresbury laboratory. The structure has been solved by molecular replacement calculations using this synchrotron data and our previously determined Crithidia fasciculata enzyme structure as a search model. The space group has been identified as P4(3) with a homodimer of approximate molecular mass of 108 kDa in the asymmetric unit. Diffraction beyond 2.5 A has been recorded when large freshly grown crystals are exposed to X-rays. Refinement of the structure is in progress.
Publisher: Elsevier BV
Date: 06-1992
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for James Naismith.