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Structure of human porphobilinogen deaminase at 2.8 angstrom: the molecular basis of acute intermittent porphyria

Gill, R; Kolstoe, SE; Mohammed, F; Al D-Bass, A; Mosely, JE; Sarwar, M; Cooper, JB; ... Shoolingin-Jordan, PM; + view all (2009) Structure of human porphobilinogen deaminase at 2.8 angstrom: the molecular basis of acute intermittent porphyria. BIOCHEM J , 420 17 - 25. 10.1042/BJ20082077.

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Abstract

Mutations in the human PBGD (porphobilinogen deaminase) gene cause the inherited defect AIP (acute intermittent porphyria). In the present study we report the structure of the human uPBGD (ubiquitous PBGD) mutant, R167Q, that has been determined by X-ray crystallography and refined to 2.8 angstrom (1 angstrom = 0.1 nm) resolution (R-factor = 0.26, R-free = 0.29). The protein crystallized in space group P2(1)2(1)2 with two molecules in the asymmetric unit (a = 8 1.0 angstrom., b = 104.4 A and c = 109.7 angstrom). Phases were obtained by molecular replacement using the Escherichia coli PBGD structure as a search model. The human enzyme is composed of three domains each of approx. 110 amino acids and possesses a dipyrromethane cofactor at the active site, which is located between domains 1 and 2. An ordered sulfate ion is hydrogen-bonded to Arg(26) and Ser(28) at the proposed substrate-binding site in domain 1. An insert of 29 amino acid residues, present only in mammalian PBGD enzymes, has been modelled into domain 3 where it extends helix alpha 2(3) and forms beta-hairpin structure that contributes to a continuous hydrogen-bonding network spanning domains 1 and 3. The structural and functional implications of the R167Q mutation and other mutations that result in AIP are discussed.

Type: Article
Title: Structure of human porphobilinogen deaminase at 2.8 angstrom: the molecular basis of acute intermittent porphyria
DOI: 10.1042/BJ20082077
Keywords: acute intermittent porphyria, dipyrromethane, haem, human porphobilinogen deaminase, X-ray structure, ESCHERICHIA-COLI, DIPYRROMETHANE COFACTOR, HYDROXYMETHYLBILANE SYNTHASE, PROTEIN INTERFACES, SUBSTRATE BINDING, ARGININE RESIDUES, CATALYTIC SITE, GENE, MUTATIONS, SEQUENCE
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/142982
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