Allosteric pocket

Fig. 11. Conformational changes in Eg5 upon binding of monastrol leading to the formation of the allosteric pocket, (a) KSP ADP cocrystal structure(PDB ID 1116) with key secondary structure marked, (b) KSP ADP monastrol costructure (PDB ID 1QOB) showing the movement of Loop 5 and the translocation of Trp127 by approximately 10 A the monastrol...

Fig. 12. Location of the allosteric pocket in relation to the ATP-binding pocket using the KSP ADP monastrol costructure (PDB ID 1Q0B). Key interactions between the ADP and the protein and the monastrol and the protein are shown with dashed line. Due to the complexity of the figure, distances are omitted.

Fig. 13. Chemical structures for allosteric and ATP-competitive Eg5 inhibitors, (a) Monastrol ((S)-ethyl 1,2,3,4-tetrahydro-4-(3-hydroxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxylate), the first compound discovered which bound to the allosteric pocket the compound has an IC50 of 22 uM. (b) CK-f 06023 (N-((R)-f-(3-benzyl-7-chloro-3,4-dihydro-4-oxoquinazolin-2-yl)propyl)-4-bromo-N-(3-(dimethylamino)propyl) benzamide), which binds to the same allosteric pocket as Monastrol and has a Ki of f 2 nM. (c) CK-238273 N-(3-aminopropyl)-N-((R)-f -(3-benzyl-7-chloro-3,4-dihydro-4-oxoquinazolin-2-yl)-2-methylpropyl)-4-methylbenzamide), an optimized analog of CK-f 06023 which is in phase II and has a Ki of f. 7 nM. (d) 4-(2-(f -phenylethyl)thiazol-4-yl)pyridine, an ATP-competitive thiazole compound which was an initial hit from the Merck compound collection the compound has an IC50 of f f uM. (e) 4-(2-(f -(4-chlorophenyl)cyclo-propyl)thiazol-4-yl)pyridine, an optimized ATP-competitive thiazole compound with an IC50 of 290 nM.

Predicting Unknown or Allosteric Pockets with ICM PocketFinder... 

In its most complete version, the Pocketome must be completed by likely cavities and allosteric pockets even if crystallo-graphically no small molecules have ever been observed in these cavities. We designed a pocket prediction algorithm based on a physical field, yet very general and relatively independent on the chemical nature of the ligand. This method, called ICM Pocket-Finder, performs the Gaussian convolution of the Lennard-Jones... 

GABAa is a protein with a pentameiic group of subunits (Fig. 4.7). Each subunit has approximately 200 amino acids. There are arormd fom hydrophobic regions which enable the receptor to possess allosteric pockets for interactions, and the hydrophobic region is also important to anchor the protein into the cell membrane. Barbiturates bind with a site different from the site of binding of benzodiazepines, which bind at the active site rather than changing the receptor conformation via an allosteric interaction. 

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