Published:
Proceedings of the National Academy of Sciences, 2020
Published in:
Proceedings of the National Academy of Sciences, 117 (2020) 50, Seite 31838-31849
Language:
English
DOI:
10.1073/pnas.2013473117
ISSN:
0027-8424;
1091-6490
Origination:
Footnote:
Description:
Significance We present a comprehensive structural study, which shows the human GCH1 and GCH1−GFRP complexes in all states (apo, ligand bound, partially and fully inhibited). We observed local rearrangements in the allosteric pocket upon BH4 binding, which result in drastic changes in the quaternary structure of the enzyme leading to a more compact, tense form in the inhibited protein. Inhibition of the enzymatic activity is not a result of hindrance of substrate binding, but rather a consequence of accelerated substrate binding kinetics as shown by STD-NMR and site-directed mutagenesis. We propose a dissociation rate-controlled mechanism of allosteric, noncompetitive inhibition, which could stimulate further research toward the development of GCH1 inhibitors to treat neuropathic and inflammatory pain disorders.