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1.
Filippo Genovese Stefania Ferrari Giambattista Guaitoli Monica Caselli M. Paola Costi Glauco Ponterini 《Protein science : a publication of the Protein Society》2010,19(5):1023-1030
An ad hoc bioconjugation/fluorescence resonance energy transfer (FRET) assay has been designed to spectroscopically monitor the quaternary state of human thymidylate synthase dimeric protein. The approach enables the chemoselective engineering of allosteric residues while preserving the native protein functions through reversible masking of residues within the catalytic site, and is therefore suitable for activity/oligomerization dual assay screenings. It is applied to tag the two subunits of human thymidylate synthase at cysteines 43 and 43′ with an excitation energy donor/acceptor pair. The dimer–monomer equilibrium of the enzyme is then characterized through steady‐state fluorescence determination of the intersubunit resonance energy transfer efficiency. 相似文献
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Costi R Di Santo R Artico M Roux A Ragno R Massa S Tramontano E La Colla M Loddo R Marongiu ME Pani A La Colla P 《Bioorganic & medicinal chemistry letters》2004,14(7):1745-1749
A series of 6-aryl-2,4-dioxo-5-hexenoic acids, were synthesized and tested against HIV-1 in cell-based assays and against recombinant HIV-1 integrase (rIN) in enzyme assays. Compound 8a showed potent antiretroviral activity (EC(50)=1.5 microM) and significant inhibition against rIN (strand transfer: IC(50)=7.9 microM; 3'-processing: IC(50)=7.0 microM). A preliminary molecular modeling study was carried out to compare the spatial conformation of 8a with those of L-731988 (4) and 5CITEP (7) in the IN core. 相似文献
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Ghelli S Rinaldi M Barlocco D Gelain A Pecorari P Tondi D Rastelli G Costi MP 《Bioorganic & medicinal chemistry》2003,11(6):951-963
Thymidylate synthase (TS) (EC 2.1.1.45), an enzyme involved in the DNA synthesis of both prokaryotic and eukaryotic cells, is a potential target for the development of anticancer and antinfective agents. Recently, we described a series of phthalein and naphthalein derivatives as TS inhibitors. These compounds have structures unrelated to the folate (Non-Analogue Antifolate Inhibitors, NAAIs) and were selective for the bacterial versus the human TS (hTS). In particular, halogen-substituted molecules were the most interesting. In the present paper the halogen derivatives of variously substituted 3,3-bis(4-hydroxyphenyl)-1H,3H-naphtho[2,3-c]furan-1-one (1-5) and 3,3-bis(4-hydroxyphenyl)-1H,3H-naphtho[1,8-c,d]pyran-1-one (6-14) were synthesized to investigate the biological effect of halogen substitution on the inhibition and selectivity for the TS enzymes. Conformational properties of the naphthalein series were explored in order to highlight possible differences between molecules that show species-specific biological profile with respect to non species-specific ones. With this aim, the conformational properties of the synthesized compounds were investigated by NMR, in various solvents and at different temperatures, and by computational analysis. The apparent inhibition constants (K(i)) for Lactobacillus casei TS (LcTS) were found to range from 0.7 to 7.0 microM, with the exception of the weakly active iodo-derivatives (4, 10, 13); all] the compounds were poorly active against hTS. The di-halogenated compounds 7, 8, 14 showed the highest specificity towards LcTS, their specificity index (SI) ranging between 40 and >558. The di-halogenated 1,8-naphthalein derivatives (7-10) exhibited different conformational properties with respect to the tetra-haloderivatives. Though a clear explanation for the observed specificity by means of conformational analysis is difficult to find, some interesting conformational effects are discussed in the context of selective recognition of the compounds investigated by the LcTS enzyme. 相似文献
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D Taruscio C Morciano P Laricchiuta P Mincarone F Palazzo CG Leo S Sabina R Guarino J Auld T Sejersen D Gavhed K Ritchie M Hilton-Boon J Manson PG Kanavos D Tordrup V Tzouma Y Le Cam J Senecat G Filippini S Minozzi C Del Giovane H Schünemann JJ Meerpohl B Prediger L Schell R Stefanov G Iskrov T Miteva-Katrandzhieva P Serrano-Aguilar L Perestelo-Perez MM Trujillo-Martín J Pérez-Ramos A Rivero-Santana A Brand H van Kranen K Bushby A Atalaia J Ramet L Siderius M Posada I Abaitua-Borda V Alonso Ferreira M Hens-Pérez FJ Manzanares 《Orphanet journal of rare diseases》2014,9(Z1):O14
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Costi JJ Stokes IA Gardner-Morse M Laible JP Scoffone HM Iatridis JC 《Journal of biomechanics》2007,40(11):2457-2466
Human intervertebral disc specimens were tested to determine the regions of largest maximum shear strain (MSS) experienced by disc tissues in each of three principal displacements and three rotations, and to identify the physiological rotations and displacements that may place the disc at greatest risk for large tissue strains and injury. Tearing of disc annulus may be initiated by large interlamellar shear strains. Nine human lumbar discs were tagged with radiographic markers on the endplates, disc periphery and with a grid of wires in the mid-transverse plane and subjected to each of the six principal displacements and rotations. Stereo-radiographs were taken in each position and digitized for reconstruction of the three-dimensional position of each marker. Maximum tissue shear strains were calculated from relative marker displacements and normalized by the input displacement or rotation. Lateral shear, compression, and lateral bending were the motions that produced the mean (95% confidence interval) largest mean MSS of 9.6 (0.7)%/mm, 9.0 (0.5)%/mm, and 5.8 (1.6)%/ degrees , respectively, and which occurred in the posterior, posterolateral and lateral peripheral regions of the disc. After taking into account the reported maximum physiological range of motion for each degree of freedom, motions producing the highest physiological MSS were lateral bending (57.8 (16.2)%) and flexion (38.3 (3.3)%), followed by lateral shear (14.4 (1.1)%) and compression (12.6 (0.7)%). 相似文献