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Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase.

ABSTRACT: The O-linked ?-N-acetyl glucosamine (O-GlcNAc) modification dynamically regulates the functions of numerous proteins. A single human enzyme O-linked ?-N-acetyl glucosaminase (O-GlcNAcase or OGA) hydrolyzes this modification. To date, it remains largely unknown how OGA recognizes various substrates. Here we report the structures of OGA in complex with each of four distinct glycopeptide substrates that contain a single O-GlcNAc modification on a serine or threonine residue. Intriguingly, these glycopeptides bind in a bidirectional yet conserved conformation within the substrate-binding cleft of OGA. This study provides fundamental insights into a general principle that confers the substrate binding adaptability and specificity to OGA in O-GlcNAc regulation.O-linked ?-N-acetyl glucosamine (O-GlcNAc) is an important protein modification that is hydrolyzed by O-GlcNAcase (OGA). Here the authors give insights into OGA substrate recognition by presenting four human OGA structures complexed with glycopeptide substrates containing a single O-GlcNAc modification on either a serine or threonine.

SUBMITTER: Li B

PROVIDER: S-EPMC5610315 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase.

Li Baobin B Li Hao H Hu Chia-Wei CW Jiang Jiaoyang J

Nature communications 20170922 1

The O-linked β-N-acetyl glucosamine (O-GlcNAc) modification dynamically regulates the functions of numerous proteins. A single human enzyme O-linked β-N-acetyl glucosaminase (O-GlcNAcase or OGA) hydrolyzes this modification. To date, it remains largely unknown how OGA recognizes various substrates. Here we report the structures of OGA in complex with each of four distinct glycopeptide substrates that contain a single O-GlcNAc modification on a serine or threonine residue. Intriguingly, these gly ...[more]

PMID: 28939839

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Project description:Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of electrolyte balance and blood pressure. Excess aldosterone levels can arise from dysregulation of the renin-angiotensin-aldosterone system and are implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (cytochrome P450 11B2, CYP11B2) is the sole enzyme responsible for the production of aldosterone in humans. Blocking of aldosterone synthesis by mediating aldosterone synthase activity is thus a recently emerging pharmacological therapy for hypertension, yet a lack of structural information has limited this approach. Here, we present the crystal structures of human aldosterone synthase in complex with a substrate deoxycorticosterone and an inhibitor fadrozole. The structures reveal a hydrophobic cavity with specific features associated with corticosteroid recognition. The substrate binding mode, along with biochemical data, explains the high 11β-hydroxylase activity of aldosterone synthase toward both gluco- and mineralocorticoid formation. The low processivity of aldosterone synthase with a high extent of intermediates release might be one of the mechanisms of controlled aldosterone production from deoxycorticosterone. Although the active site pocket is lined by identical residues between CYP11B isoforms, most of the divergent residues that confer additional 18-oxidase activity of aldosterone synthase are located in the I-helix (vicinity of the O(2) activation path) and loops around the H-helix (affecting an egress channel closure required for retaining intermediates in the active site). This intrinsic flexibility is also reflected in isoform-selective inhibitor binding. Fadrozole binds to aldosterone synthase in the R-configuration, using part of the active site cavity pointing toward the egress channel. The structural organization of aldosterone synthase provides critical insights into the molecular mechanism of catalysis and enables rational design of more specific antihypertensive agents.

Dataset Information

Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase.

Publications

Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase.

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