Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small molecule inhibitor of the E2 ubiquitin conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester, without overtly affecting the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.
The low temperature modifications of the normal paraffins n-CnH2n+2crystallize in three groups (Broadhurst, 1962). The structure is triclinic for n even, 6 < n < 26 (Muller and Lonsdale, 1948; Nyburg and Luth, 1972); orthorhombic for n odd, 11 < n < 39 (Smith, 1953; Teare, 1959); and monoclinic for n even, 28 < n < 36 (Shearer and Vand, 1956). In all of these structures the hydrocarbon chains are linear and in trans configuration. The chains are parallel to one another, the terminal methyl groups forming the surfaces of lamella which are more or less perpendicular to the chain axis. For n < ca.36, it is apparently the interlamellar interaction between end methyl groups which dictates the symmetry. For longer chains the structure is usually orthorhombic and comparable to the structure of highly crystalline polyethylenes. Chains do not fold (as they undoubtedly do in polyethylenes) unless n is greater than 102 (Bidd and Whiting, 1985; Ungar and Keller, 1986).The several crystal forms differ in the manner in which the nearest neighbor chains are related to one another. In the triclinic lattices the packing is such that a triclinic sublattice containing one methylene group is evident. In the other modifications the sublattice is orthorhombic and contains four methylene groups. If the overall symmetry is orthorhombic the long chain axes are perpendicular to the interlamellar surface; the x and y translations, perpendicular to the long axis, are common to both cells. If the nearest neighbor chains are displaced by two or four methylene groups along the chain axis, overall monoclinic symmetry results (Sullivan and Weeks (1970)).
1,3-Dipolar cycloadditions of mesoionic 1,3-dipoles (Münchnones, imino-Münchnones, and phospha-Münchnones) with alkynes offer versatile, modular synthetic routes to pyrroles. Reactivity and regioselectivity differ markedly for different members of this series, and we report here the first general rationale for differences in reactivity by means of a systematic investigation of 1,3-dipolar cycloadditions involving electron-poor and electron-rich alkynes. Competition kinetic measurements indicate that Münchnones and phospha-Münchnones are nucleophilic 1,3-dipoles that react most rapidly with electron-poor alkynes. However, the regioselectivities of cycloadditions are found to undergo an inversion as a function of alkyne ionization potential. The exact point at which this occurs is different for the two dipoles, allowing rational control of the pyrrole formed. The origins of these reactivities and regioselectivities are examined computationally. Frontier molecular orbital predictions are found not to be accurate for these reactions, but transition state calculations give correct predictions of reactivity and selectivity, the origins of which can be analyzed using the distortion/interaction model of reactivity. Cycloadditions with electron-poor alkynes are shown to favor the regioisomer that has either the most favorable TS interaction energy (Münchnones or imino-Münchnones) or the smallest TS distortion energy (phospha-Münchnones). Cycloadditions with more electron-rich aryl-substituted alkynes, on the other hand, generally favor the regioisomer that has the smaller TS distortion energy. These insights delineate the synthetically important distinctions between Münchnones and phospha-Münchnones: phospha-Münchnones undergo highly regioselective cycloadditions with electron-poor alkynes that do not react selectively with Münchnones, and the reverse is true for cycloadditions of Münchnones with electron-rich alkynes.
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