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Issue 19, 2017
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A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site

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Abstract

The turnstile motion of two neighboring threonines sets up a dynamic side chain interplay that can accommodate both polar and apolar ligands in a small molecule allosteric protein binding site. A computational model based on SAR data and both X-ray and cryo-EM structures of the AAA ATPase p97 was used to analyze the effects of paired threonines at the inhibitor site. Specifically, the Thr side chain hydroxyl groups form a hydrogen bonding network that readily accommodates small, highly polar ligand substituents. Conversely, diametric rotation of the χ1 torsion by 150–180° orients the side chain β-methyl groups into the binding cleft, creating a hydrophobic pocket that can accommodate small, apolar substituents. This motif was found to be critical for rationalizing the affinities of a structurally focused set of inhibitors of p97 covering a > 2000-fold variation in potencies, with a preference for either small-highly polar or small-apolar groups. The threonine turnstile motif was further validated by a PDB search that identified analogous binding modes in ligand interactions in PKB, as well as by an analysis of NMR structures demonstrating additional gear-like interactions between adjacent Thr pairs. Combined, these data suggest that the threonine turnstile motif may be a general feature of interest in protein binding pockets.

Graphical abstract: A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site

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Publication details

The article was received on 01 Mar 2017, accepted on 20 Mar 2017 and first published on 22 Mar 2017


Article type: Paper
DOI: 10.1039/C7OB00526A
Citation: Org. Biomol. Chem., 2017,15, 4096-4114
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    A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site

    J. C. Burnett, C. Lim, B. D. Peyser, L. P. Samankumara, M. Kovaliov, R. Colombo, S. L. Bulfer, M. G. LaPorte, A. R. Hermone, C. F. McGrath, M. R. Arkin, R. Gussio, D. M. Huryn and P. Wipf, Org. Biomol. Chem., 2017, 15, 4096
    DOI: 10.1039/C7OB00526A

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