ArticleBiochemistry2009
Altered enthalpy-entropy compensation in picomolar transition state analogues of human purine nucleoside phosphorylase.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 57 citations in OpenAlex.
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- Extreme enthalpy‒entropy compensation in the dimerization of small solutes in aqueous solution.European biophysics journal : EBJ · 2024Review
- Snapshots of the Reaction Coordinate of a Thermophilic 2'-Deoxyribonucleoside/ribonucleoside Transferase.ACS catalysis · 2024Article
- Phosphate Binding in PNP Alters Transition-State Analogue Affinity and Subunit Cooperativity.Biochemistry · 2023Article
- Binding thermodynamics and interaction patterns of human purine nucleoside phosphorylase-inhibitor complexes from extensive free energy calculations.Journal of computer-aided molecular design · 2021Article
- Enzymatic Transition States and Drug Design.Chemical reviews · 2018Review
- Flexibility vs rigidity of amphipathic peptide conjugates when interacting with lipid bilayers.Biochimica et biophysica acta. Biomembranes · 2017Article
- Intracellular rebinding of transition-state analogues provides extendedThe Journal of biological chemistry · 2017Article
- Enthalpy-entropy compensation: the role of solvation.European biophysics journal : EBJ · 2017Review
- Heat Capacity Changes for Transition-State Analogue Binding and Catalysis with Human 5'-Methylthioadenosine Phosphorylase.ACS chemical biology · 2017Article
- Natural Products as New Treatment Options for Trichomoniasis: A Molecular Docking Investigation.Scientia pharmaceutica · 2017Article
- Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell.Chemical reviews · 2016Review
- Transition States and transition state analogue interactions with enzymes.Accounts of chemical research · 2015Article
- Thermodynamic analysis of transition-state features in picomolar inhibitors of human 5'-methylthioadenosine phosphorylase.Biochemistry · 2013Article
- Distortional binding of transition state analogs to human purine nucleoside phosphorylase probed by magic angle spinning solid-state NMR.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Transition-state inhibitors of purine salvage and other prospective enzyme targets in malaria.Future medicinal chemistry · 2013Review
- Catalytic site conformations in human PNP by 19F-NMR and crystallography.Chemistry & biology · 2013Article
- Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics.Bioorganic & medicinal chemistry · 2012Article
- Multiple cholesterol recognition/interaction amino acid consensus (CRAC) motifs in cytosolic C tail of Slo1 subunit determine cholesterol sensitivity of Ca2+- and voltage-gated K+ (BK) channels.The Journal of biological chemistry · 2012Article
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6 authors at 1 institution in 1 country.
Funding
Abstract
Human purine nucleoside phosphorylase (PNP) belongs to the trimeric class of PNPs and is essential for catabolism of deoxyguanosine. Genetic deficiency of PNP in humans causes a specific T-cell immune deficiency, and transition state analogue inhibitors of PNP are in development for treatment of T-cell cancers and autoimmune disorders. Four generations of Immucillins have been developed, each of which contains inhibitors binding with picomolar affinity to human PNP. Full inhibition of PNP occurs upon binding to the first of three subunits, and binding to subsequent sites occurs with negative cooperativity. In contrast, substrate analogue and product bind without cooperativity. Titrations of human PNP using isothermal calorimetry indicate that binding of a structurally rigid first-generation Immucillin (K(d) = 56 pM) is driven by large negative enthalpy values (DeltaH = -21.2 kcal/mol) with a substantial entropic (-TDeltaS) penalty. The tightest-binding inhibitors (K(d) = 5-9 pM) have increased conformational flexibility. Despite their conformational freedom in solution, flexible inhibitors bind with high affinity because of reduced entropic penalties. Entropic penalties are proposed to arise from conformational freezing of the PNP.inhibitor complex with the entropy term dominated by protein dynamics. The conformationally flexible Immucillins reduce the system entropic penalty. Disrupting the ribosyl 5'-hydroxyl interaction of transition state analogues with PNP causes favorable entropy of binding. Tight binding of the 17 Immucillins is characterized by large enthalpic contributions, emphasizing their similarity to the transition state. Via introduction of flexibility into the inhibitor structure, the enthalpy-entropy compensation pattern is altered to permit tighter binding.
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