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Molecular Pharmacology

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Research ArticleArticle

A Molecular Model of the Human UDP-Glucuronosyltransferase 1A1, Its Membrane Orientation, and the Interactions between Different Parts of the Enzyme

Liisa Laakkonen and Moshe Finel
Molecular Pharmacology June 2010, 77 (6) 931-939; DOI: https://doi.org/10.1124/mol.109.063289
Liisa Laakkonen
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Moshe Finel
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Abstract

The vertebrate UDP-glucuronosyltransferases (UGTs) are membrane-bound enzymes of the endoplasmic reticulum that process both endogenous and exogenous substrates. The human UGTs are well known biologically, but biophysical understanding is scarce, largely because of problems in purification. The one resolved crystal structure covers the C-terminal domain of the human UGT2B7. Here, we present a homology model of the complete monomeric human UGT1A1, the enzyme that catalyzes bilirubin glucuronidation. The enzyme can be seen as composed of four different domains: two large ones, the N- and C-terminal domains, and two small ones, the “envelope” helices and the transmembrane segment that includes the cytoplasmic tail. The hydrophobic core of the N-terminal domain and the two envelope helices that connect the large domains are shown to be structurally well conserved even among distant homologs and can thus be modeled with good certainty according to plant and bacterial structures. We consider alternative solutions for the highly variable N-terminal regions that probably contribute to substrate binding. The bilirubin binding site, known pathological mutations in UGT1A1, and other specific residues have been examined in the context of the model with regard to available experimental data. A putative orientation of the protein relative to the membrane has been derived from the location of predicted N-glycosylation sites. The model presents extensive interactions between the N- and C-terminal domains, the two envelope helices, and the membrane. Together, these interactions could allow for a concerted large-scale conformational change during catalysis.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Sigrid Juselius Foundation and the Magnus Ehrnrooth Foundation.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.063289.

  • ABBREVIATIONS:

    UGT
    UDP-glucuronosyltransferase
    GT
    glycosyltransferase
    PDB
    Protein Data Bank
    CN-I
    Crigler-Najjar type I
    CN-II
    Crigler-Najjar type II.

  • Received December 22, 2009.
  • Accepted March 9, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (6)
Molecular Pharmacology
Vol. 77, Issue 6
1 Jun 2010
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Research ArticleArticle

A Molecular Model of the Human UDP-Glucuronosyltransferase 1A1, Its Membrane Orientation, and the Interactions between Different Parts of the Enzyme

Liisa Laakkonen and Moshe Finel
Molecular Pharmacology June 1, 2010, 77 (6) 931-939; DOI: https://doi.org/10.1124/mol.109.063289

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Research ArticleArticle

A Molecular Model of the Human UDP-Glucuronosyltransferase 1A1, Its Membrane Orientation, and the Interactions between Different Parts of the Enzyme

Liisa Laakkonen and Moshe Finel
Molecular Pharmacology June 1, 2010, 77 (6) 931-939; DOI: https://doi.org/10.1124/mol.109.063289
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