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2i4t

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{{STRUCTURE_2i4t| PDB=2i4t | SCENE= }}
{{STRUCTURE_2i4t| PDB=2i4t | SCENE= }}
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'''Crystal stucture of Purine Nucleoside Phosphorylase from Trichomonas vaginalis with Imm-A'''
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===Crystal stucture of Purine Nucleoside Phosphorylase from Trichomonas vaginalis with Imm-A===
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==Overview==
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Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition state mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a Km/Kd ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a Km/Kd ratio of 203,300. The tight binding of DADMe-ImmA supports a late SN1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP x ImmA x PO4 and TvPNP x DADMe-ImmA x PO4 ternary complexes differ from previous structures with substrate analogues. The tight binding with DADMe-ImmA is in part due to a 2.7 A ionic interaction between a PO4 oxygen and the N1' cation of the hydroxypyrrolidine and is weaker in the TvPNP x ImmA x PO4 structure at 3.5 A. However, the TvPNP x ImmA x PO4 structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP x DADMe-ImmA x PO4. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope-edited difference infrared spectroscopy with [6-18O]ImmH to establish that O6 is the keto tautomer in TvPNP x ImmH x PO4, causing an unfavorable leaving-group interaction.
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==About this Structure==
==About this Structure==
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[[Category: Schramm, V L.]]
[[Category: Schramm, V L.]]
[[Category: Purine nucleoside phosphorylase]]
[[Category: Purine nucleoside phosphorylase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 06:21:49 2008''

Revision as of 03:21, 28 July 2008

Image:2i4t.png

Template:STRUCTURE 2i4t

Crystal stucture of Purine Nucleoside Phosphorylase from Trichomonas vaginalis with Imm-A

Template:ABSTRACT PUBMED 17223688

About this Structure

Full crystallographic information is available from OCA.

Reference

Inhibition and structure of Trichomonas vaginalis purine nucleoside phosphorylase with picomolar transition state analogues., Rinaldo-Matthis A, Wing C, Ghanem M, Deng H, Wu P, Gupta A, Tyler PC, Evans GB, Furneaux RH, Almo SC, Wang CC, Schramm VL, Biochemistry. 2007 Jan 23;46(3):659-68. PMID:17223688

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