ORCID Profile
0000-0002-1370-0896
Current Organisation
University of Southampton
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Publisher: Wiley
Date: 27-12-2022
Abstract: Glycosyltransferases are a superfamily of enzymes that are notoriously difficult to inhibit. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non‐standard peptides integrated discovery) system, to identify macrocyclic peptides with high binding affinities for O‐GlcNAc transferase (OGT). These macrocycles inhibit OGT activity through an allosteric mechanism that is driven by their binding to the tetratricopeptide repeats of OGT. Saturation mutagenesis in a maturation screen using 39 amino acids, including 22 non‐canonical residues, led to an improved unnatural macrocycle that is ≈40 times more potent than the parent compound ( K i app =1.5 nM). Subsequent derivatization delivered a biotinylated derivative that enabled one‐step affinity purification of OGT from complex s les. The high potency and novel mechanism of action of these OGT ligands should enable new approaches to elucidate the specificity and regulation of OGT.
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3SC01594G
Publisher: Wiley
Date: 02-04-2020
Publisher: Wiley
Date: 27-12-2022
Abstract: Glycosyltransferases are a superfamily of enzymes that are notoriously difficult to inhibit. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non‐standard peptides integrated discovery) system, to identify macrocyclic peptides with high binding affinities for O‐GlcNAc transferase (OGT). These macrocycles inhibit OGT activity through an allosteric mechanism that is driven by their binding to the tetratricopeptide repeats of OGT. Saturation mutagenesis in a maturation screen using 39 amino acids, including 22 non‐canonical residues, led to an improved unnatural macrocycle that is ≈40 times more potent than the parent compound ( K i app =1.5 nM). Subsequent derivatization delivered a biotinylated derivative that enabled one‐step affinity purification of OGT from complex s les. The high potency and novel mechanism of action of these OGT ligands should enable new approaches to elucidate the specificity and regulation of OGT.
Publisher: Wiley
Date: 02-04-2020
Publisher: American Society for Microbiology
Date: 18-12-2020
DOI: 10.1128/JB.00434-20
Abstract: M48 metalloproteases are widely distributed in all domains of life. E. coli possesses four members of this family located in multiple cellular compartments. The functions of these proteases are not well understood. Recent investigations revealed that one family member, BepA, has an important role in the maturation of a central component of the lipopolysaccharide (LPS) biogenesis machinery. Here, we present the structure of BepA and the results of a structure-guided mutagenesis strategy, which reveal the key residues required for activity that inform how all M48 metalloproteases function.
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
No related grants have been discovered for Richard Meek.