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Structural and Functional Analysis of Peptidyl Oligosaccharyl Transferase Inhibitors

Kellenberger, Christine and Hendrickson, Tamara L. and Imperiali, Barbara (1997) Structural and Functional Analysis of Peptidyl Oligosaccharyl Transferase Inhibitors. Biochemistry, 36 (41). pp. 12554-12559. ISSN 0006-2960. doi:10.1021/bi971465d.

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The peptide cyclo(hex-Amb_(1)-Cys_(2))-Thr_(3)-Val_(4)-Thr_(5)-Nph_(6)-NH_2 was previously shown to be a slow, tight-binding inhibitor (Ki = 37 nM) of the yeast oligosaccharyl transferase (OT) [Hendrickson et al. (1996) J. Am. Chem. Soc. 118, 7636−7637]. This enzyme catalyzes the transfer of a carbohydrate moiety to an asparagine residue in the consensus sequence Asn-Xaa-Thr/Ser. Herein we present a study of the contribution of the residues in positions 1, 3, 4, and 5 to OT binding. Replacement of the threonine (residue 3) by valine or (S)-2-aminobutyric acid dramatically reduced the potency of the inhibitor while, surprisingly, the incorporation of an additional methylene into the side chain of residue 1 [(S)-2,3-diaminobutyric acid changed to ornithine] had very little effect. Variants with acidic, basic, hydrophilic/polar, and hydrophobic side chains in positions 4 and 5 were also evaluated for both yeast and porcine liver OT inhibition. This aspect of the study reveals that basic (lysine) and acidic (glutamic acid) residues are detrimental to the binding, whereas hydrophobic (valine) and polar/hydrophilic (threonine) residues are both well tolerated. The kinetic behavior of substrate analogs [cyclo(hex-Asn_(1)-Cys_(2))-Thr_(3)-Xaa_(4)-Yaa_(5)-Nph-NH_2] corresponding to inhibitors of weak, medium, and strong potency was also examined in order to provide insight into the nature of these inhibitors.

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Additional Information:© 1997 American Chemical Society. Received 18 June 1997. Published online 14 October 1997. This work was supported by the National Institutes of Health (GM39334) and an A. C. Cope Scholar Award to B.I.
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Issue or Number:41
Record Number:CaltechAUTHORS:20180213-080313940
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Official Citation:Structural and Functional Analysis of Peptidyl Oligosaccharyl Transferase Inhibitors Christine Kellenberger, Tamara L. Hendrickson, and Barbara Imperiali Biochemistry 1997 36 (41), 12554-12559 DOI: 10.1021/bi971465d
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84801
Deposited By: Ruth Sustaita
Deposited On:13 Feb 2018 20:58
Last Modified:15 Nov 2021 20:23

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