Conformational dynamics in human purine nucleoside phosphorylase with reactants and transition-state analogues

Jennifer S. Hirschi, Karunesh Arora, Charles L. Brooks, Vern L. Schramm

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Dynamic motions of human purine nucleoside phosphorylase (hPNP) in complex with transition-state analogues and reactants were studied using 10 ns explicit solvent molecular dynamics simulations. hPNP is a homotrimer that catalyzes the phosphorolysis of purine 6-oxynucleosides. The ternary complex of hPNP includes the binding of a ligand and phosphate to the active site. Molecular dynamics simulations were performed on the ternary complex of six ligands including the picomolar transition-state analogues, Immucillin-H (Kd = 56 pM), DADMe-Immucillin-H (Kd = 8.5 pM), DATMe-Immucillin-H (Kd = 8.6 pM), SerMe-Immucillin-H (Kd = 5.2 pM), the substrate inosine, and a complex containing only phosphate. Protein-inhibitor complexes of the late transition-state inhibitors, DADMe-Imm-H and DATMe-Imm-H, are inflexible. Despite the structural similarity of SerMe-Imm-H and DATMe-Imm-H, the protein complex of SerMe-Imm-H is flexible, and the inhibitor is highly mobile within the active sites. All inhibitors exhibit an increased number of nonbonding interactions in the active site relative to the substrate inosine. Water density within the catalytic site is lower for DADMe-ImmH, DATMe-Imm-H, and SerMe-Imm-H than that for the substrate inosine. Tight binding of the picomolar inhibitors results from increased interactions within the active site and a reduction in the number of water molecules organized within the catalytic site relative to the substrate inosine.

Original languageEnglish (US)
Pages (from-to)16263-16272
Number of pages10
JournalJournal of Physical Chemistry B
Volume114
Issue number49
DOIs
StatePublished - Dec 16 2010

Fingerprint

Purine-Nucleoside Phosphorylase
Inosine
purines
nucleosides
inhibitors
analogs
Substrates
Molecular dynamics
Phosphates
Ligands
Proteins
Water
phosphates
Computer simulation
molecular dynamics
proteins
ligands
water
Molecules
Nucleosides

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Materials Chemistry
  • Surfaces, Coatings and Films

Cite this

Conformational dynamics in human purine nucleoside phosphorylase with reactants and transition-state analogues. / Hirschi, Jennifer S.; Arora, Karunesh; Brooks, Charles L.; Schramm, Vern L.

In: Journal of Physical Chemistry B, Vol. 114, No. 49, 16.12.2010, p. 16263-16272.

Research output: Contribution to journalArticle

Hirschi, Jennifer S. ; Arora, Karunesh ; Brooks, Charles L. ; Schramm, Vern L. / Conformational dynamics in human purine nucleoside phosphorylase with reactants and transition-state analogues. In: Journal of Physical Chemistry B. 2010 ; Vol. 114, No. 49. pp. 16263-16272.
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