Molecular dynamics and energetic perceptions of substrate recognition by thymidylate kinase

Kandeel, Mahmoud; Noguchi, Yoshihiro; Oh‐hashi, Kentaro; Kim, Hye Sook; Kitade, Yukio

doi:10.1007/s10973-013-3319-5

Cited by 4 publications

(1 citation statement)

References 32 publications

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“…The negative value of Δ C p is suggestive of binding to a hydrophobic buried region, as previously described for ligands with binding that involves driving solvent molecules out of a pocket . There are previous works that described positive Δ C p thermodynamics for the protein–small ligand interactions; the positive heat capacity change is thought to result when the ligand binds to an exposed nonpolar surface. , Based on the model structures, we calculated the solvent-accessible surface area (ASA) of Hsp90 in each complex. As shown in Table , the nonpolar and polar ASAs of Hsp90 in the THS-510 complex (5809.7 and 4979.4 Å 2 ) were larger than those in the TAS-116 complex (5785.9 and 4900.9 Å 2 ), respectively.…”

Section: Resultsmentioning

confidence: 99%

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors

et al. 2021

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The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.

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Section: Resultsmentioning

confidence: 99%

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors

et al. 2021

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A novel viral thymidylate kinase with dual kinase activity

Guevara-Hernández

Arvizu‐Flores

Lugo‐Sánchez

et al. 2015

J Bioenerg Biomembr

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Nucleotide phosphorylation is a key step in DNA replication and viral infections, since suitable levels of nucleotide triphosphates pool are required for this process. Deoxythymidine monophosphate (dTMP) is produced either by de novo or salvage pathways, which is further phosphorylated to deoxythymidine triphosphate (dTTP). Thymidyne monophosphate kinase (TMK) is the enzyme in the junction of both pathways, which phosphorylates dTMP to yield deoxythymidine diphosphate (dTDP) using adenosine triphosphate (ATP) as a phosphate donor. White spot syndrome virus (WSSV) genome contains an open reading frame (ORF454) that encodes a thymidine kinase and TMK domains in a single polypeptide. We overexpressed the TMK ORF454 domain (TMKwssv) and its specific activity was measured with dTMP and dTDP as phosphate acceptors. We found that TMKwssv can phosphorylate dTMP to yield dTDP and also is able to use dTDP as a substrate to produce dTTP. Kinetic parameters K M and k cat were calculated for dTMP (110 μM, 3.6 s(-1)), dTDP (251 μM, 0.9 s(-1)) and ATP (92 μM, 3.2 s(-1)) substrates, and TMKwssv showed a sequential ordered bi-bi reaction mechanism. The binding constants K d for dTMP (1.9 μM) and dTDP (10 μM) to TMKwssv were determined by Isothermal Titration Calorimetry. The affinity of the nucleotidic analog stavudine monophosphate was in the same order of magnitude (K d 3.6 μM) to the canonical substrate dTMP. These results suggest that nucleotide analogues such as stavudine could be a suitable antiviral strategy for the WSSV-associated disease.

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Evolution of camel CYP2E1 and its associated power of binding toxic industrial chemicals and drugs

Kandeel

Altaher

Kitade

et al. 2016

Computational Biology and Chemistry

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Molecular dynamics and energetic perceptions of substrate recognition by thymidylate kinase

Cited by 4 publications

References 32 publications

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors

A novel viral thymidylate kinase with dual kinase activity

Evolution of camel CYP2E1 and its associated power of binding toxic industrial chemicals and drugs

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