Conformational states of human purine nucleoside phosphorylase at rest, at work, and with transition state analogues.

Biochemistry
Achelle A EdwardsVern L Schramm

Abstract

Human purine nucleoside phosphorylase (PNP) is a homotrimer binding tightly to the transition state analogues Immucillin-H (ImmH; K(d) = 56 pM) and DATMe-ImmH-Immucillin-H (DATMe-ImmH; K(d) = 8.6 pM). ImmH binds with a larger entropic penalty than DATMe-ImmH, a chemically more flexible inhibitor. The testable hypothesis is that PNP conformational states are more relaxed (dynamic) with DATMe-ImmH, despite tighter binding than with ImmH. PNP conformations are probed by peptide amide deuterium exchange (HDX) using liquid chromatography high-resolution Fourier transform ion cyclotron resonance mass spectrometry and by sedimentation rates. Catalytically equilibrating Michaelis complexes (PNP.PO(4).inosine <--> PNP.Hx.R-1-P) and inhibited complexes (PNP.PO(4).DATMe-ImmH and PNP.PO(4).ImmH) show protection from HDX at 9, 13, and 15 sites per subunit relative to resting PNP (PNP.PO(4)) in extended incubations. The PNP.PO(4).ImmH complex is more compact (by sedimentation rate) than the other complexes. HDX kinetic analysis of ligand-protected sites corresponds to peptides near the catalytic sites. HDX and sedimentation results establish that PNP protein conformation (dynamic motion) correlates more closely with entropy of binding than w...Continue Reading

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Citations

Aug 25, 2011·Journal of the American Chemical Society·Vern L Schramm
May 8, 2013·Journal of Medicinal Chemistry·Yansong WangFelix Hausch
Oct 13, 2010·The Journal of Physical Chemistry. B·Jennifer S HirschiVern L Schramm
Feb 14, 2012·Drug Discovery Today·Patrick Chène
Nov 22, 2011·Journal of Chromatography. a·Marcela Cristina de MoraesQuezia Bezerra Cass
Apr 8, 2015·Accounts of Chemical Research·Vern L Schramm
Sep 3, 2010·Current Opinion in Chemical Biology·Dudley H Williams
Sep 9, 2010·Current Opinion in Chemical Biology·Buyong Ma, Ruth Nussinov
Jan 26, 2013·Journal of Peptide Science : an Official Publication of the European Peptide Society·John A Robinson
Apr 30, 2011·International Journal of Mass Spectrometry·Michael J ChalmersPatrick R Griffin
Dec 25, 2015·PLoS Neglected Tropical Diseases·Elisangela Oliveira FreitasClarisa B Palatnik-de-Sousa
Oct 20, 2018·Chemical Reviews·Vern L Schramm

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