HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites—Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding—are inhibitory and provide opportunities for discovery of new anti-AIDS drugs.
In a previous paper [Rossmanith (1992). Acta Cryst. A48, 596-610], new formulae for the Lorentz factor and peak width for single and multiple diffraction were given. These formulae are used in the program UMWEG90 for the calculation of if-scan simulations.In this paper, simulations are compared with five different i scans of two different zinc single-crystal spheres measured with Mo and Ag K~ radiations, respectively. It is shown that, by fitting the calculated to the measured i scans, consistent and physically significant parameters for the mosaic structure parameters -mosaic spread and mosaic-block sizeand for the divergence parameters of the X-ray beam are obtained. Moreover, it is shown that the parameters obtained from multiple-diffraction experiments are consistent with those resulting from single-diffraction experiments performed with synchrotron radiation.
Die Rontgcnstrukturanalyse des 1,6-Dipols 1 zeigt einen intramolekularen S-N-Kontakt von 236 pm, der auf Stabilisierung durch ,,no-bond"-Resonanz weist. In Umsetzungen mit den Heterocumulenen 2-5 wird der Thiazolin-Ring von 1 geoffnet; es resulticrcn die Hetcrocyclcn 7a -f, 8e. Abweichend reagiert Bis-(trimethylsilyl)thiokctcn (6): das Primaraddukt 15 ergibt iiber eine 1,3-Vcrschicbung dcr Dimethylamino-Gruppe das Produkt 16 b.Dcsscn Konstitution folgt aus dcr Rontgenstrukturanalyse des Abbauprodukts 17.
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