Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Zubrienė, Asta; Gutkowska, Małgorzata; Matulienė, Jurgita; Chaleckis, Romanas; Michailovienė, Vilma; Voroncova, Aliona; Venclovas, C̆eslovas; Żylicz, Alicja; Żylicz, Maciej; Matulis, Daumantas

doi:10.1016/j.bpc.2010.09.003

Cited by 23 publications

(30 citation statements)

References 51 publications

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“…Similar curves were previously published for radicicol [47]. The four strongly-binding ICPD compounds exhibited a large T m shift of more than 10°C.…”

Section: Resultssupporting

confidence: 84%

“…This decrease was attributed to a binding-linked protonation event. The analysis of binding-linked protonation events was done as previously described [35], [40] and applied to Hsp90 [47]–[49].…”

Section: Resultsmentioning

confidence: 99%

“…ICPD inhibitors bear resorcinol group and should bind similarly to the naturally occurring compound radicicol (PDB ID 1bgq, energetics analyzed in [47]) or inhibitors such as 4-chloro-6-(4-piperazin-1-yl-1h-pyrazol-3-yl)-benzene-1,2-diol (PDB ID 2ccs [51]). One hydroxyl group of the compound makes direct hydrogen bond with Asp93 and the nitrogen of the pyrazole ring makes the hydrogen bond with the carbonyl oxygen of Gly97.…”

Section: Discussionmentioning

confidence: 99%

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Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

et al. 2012

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The design of specific inhibitors against the Hsp90 chaperone and other enzyme relies on the detailed and correct understanding of both the thermodynamics of inhibitor binding and the structural features of the protein-inhibitor complex. Here we present a detailed thermodynamic study of binding of aryl-dihydroxyphenyl-thiadiazole inhibitor series to recombinant human Hsp90 alpha isozyme. The inhibitors are highly potent, with the intrinsic Kd approximately equal to 1 nM as determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). Dissection of protonation contributions yielded the intrinsic thermodynamic parameters of binding, such as enthalpy, entropy, Gibbs free energy, and the heat capacity. The differences in binding thermodynamic parameters between the series of inhibitors revealed contributions of the functional groups, thus providing insight into molecular reasons for improved or diminished binding efficiency. The inhibitor binding to Hsp90 alpha primarily depended on a large favorable enthalpic contribution combined with the smaller favorable entropic contribution, thus suggesting that their binding was both enthalpically and entropically optimized. The enthalpy-entropy compensation phenomenon was highly evident when comparing the inhibitor binding enthalpies and entropies. This study illustrates how detailed thermodynamic analysis helps to understand energetic reasons for the binding efficiency and develop more potent inhibitors that could be applied for therapeutic use as Hsp90 inhibitors.

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“…Similar curves were previously published for radicicol [47]. The four strongly-binding ICPD compounds exhibited a large T m shift of more than 10°C.…”

Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

et al. 2012

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“…It is important to dissect (subtract) the energetic contribution of the linked reactions from the intrinsic binding reaction. Despite the fact that most researchers limit their efforts to determining only the observed parameters at certain experimental conditions, the intrinsic thermodynamic parameters of binding have been determined for various protein-ligand systems [60][61][62][63][64][65][66].…”

Section: Discussionmentioning

confidence: 99%

Thermodynamic characterization of human carbonic anhydrase VB stability and intrinsic binding of compounds

Kasiliauskaitė

Časaitė

Juozapaitienė

et al. 2015

J Therm Anal Calorim

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The thermodynamics of low molecular weight synthetic sulfonamide inhibitor binding to carbonic anhydrase (CA) VB was determined by the isothermal titration calorimetry (ITC) and the fluorescent thermal shift assay (FTSA). ITC provided the enthalpic and entropic contributions to the binding affinity of ethoxzolamide to CA VB. FTSA is a high-throughput assay that measures protein thermal stabilization by added ligands. FTSA enabled determination of extremely high affinity of several compounds binding to CA VB. CA VB is one of two isoforms that are expressed in mitochondria, participate in carbon metabolism and pH homeostasis and are implicated in diseases such as obesity. Therefore CA VB is a drug target. Here a series of para-substituted tetrafluoro benzenesulfonamides were investigated as high affinity inhibitors of CA VB. Thermodynamic equilibrium binding measurements such as ITC and FTSA provide only the observed parameters. Dissection of binding-linked reactions is necessary to obtain the intrinsic parameters that in turn could be correlated with the chemical structure of the inhibitors. Intrinsic dissociation constants of the inhibitors were estimated and they reached 1 pM, one of the strongest binding reactions observed between any protein-ligand binding.

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“…As such, they block chaperone action by preventing the conformational rearrangements that lead to chaperone activity. Although the ATP hydrolysis cycle of hsp90s requires contributions from all three hsp90 domains, the structural basis for inhibitor affinity can be understood from studying the N-terminal domain in isolation [25, 40, 41]. In large part this is due to the fact that all of the conformational rearrangements that lead to the active state of the chaperone, including lid closure and N-terminal domain dimerization, occur subsequent to ATP binding.…”

Section: Introductionmentioning

confidence: 99%

Paralog Specific Hsp90 Inhibitors - A Brief History and a Bright Future

Gewirth

2016

CTMC

155

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Structured Abstract Background The high sequence and structural homology among the hsp90 paralogs – Hsp90α, Hsp90β, Grp94, and Trap-1 – has made the development of paralog-specific inhibitors a challenging proposition. Objective This review surveys the state of developments in structural analysis, compound screening, and structure-based design that have been brought to bear on this problem. Results First generation compounds that selectively bind to Hsp90, Grp94, or Trap-1 have been identified. Conclusion With the proof of principle firmly established, the prospects for further progress are bright.

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Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Cited by 23 publications

References 51 publications

Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

Thermodynamic characterization of human carbonic anhydrase VB stability and intrinsic binding of compounds

Paralog Specific Hsp90 Inhibitors - A Brief History and a Bright Future

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