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| - | '''Crystal stucture of Purine Nucleoside Phosphorylase from Trichomonas vaginalis with DADMe-Imm-A'''
| + | ===Crystal stucture of Purine Nucleoside Phosphorylase from Trichomonas vaginalis with DADMe-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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_17223688}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 17223688 is the PubMed ID number. |
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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]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:48:32 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 10:39:35 2008'' |
Revision as of 07:39, 28 July 2008
Template:STRUCTURE 2isc
Crystal stucture of Purine Nucleoside Phosphorylase from Trichomonas vaginalis with DADMe-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
Page seeded by OCA on Mon Jul 28 10:39:35 2008
