Covalent docking

The nucelophilicity of the activated P-lactam should be high enough to attack the carbonyl carbon of the acyl-enzyme complex and it should yield the dimeric tetrahedral intermediate TI2 (Figure 14.12). We have modeled this structure in a covalent docking step, by connecting the nitrogen of the activated P-lactam... 

Garand E, Kamrath MZ, Jordan PA, Wolk AB, McCoy AB, Miller SJ (2012) Determinatirai of non-covalent docking by IR spectroscopy of cold gas-phase complexes. Science 335 694— 698... 

Fig. 16.1 Sodium channel structure. Schematic representation of the sodium channel subunits, a, ySl and / 2. (A) The a-subunit consists of four homologous intracelIularly linked domains (I—IV) each consisting of six connected segments (1-6). The segment 4 of each of the domains acts as the voltage sensor, physically moving out in response to depolarization resulting in activation of the sodium channel. The channel is inactivated rapidly by the linker region between III and IV docking on to the acceptor site formed by the cytoplasmic ends of S5 and S6 of domain IV. The / -subunits have a common structure, with the / 1 non-covalently bound, and f 2 linked by disulfide bonds to the a-channel...

In the latter case an extraneous messenger has to dock at the receptor s extracellular binding site on the cell surface. The information about the occupancy of the corresponding receptor is transmitted through the transmembrane part of the protein into its cytosolic domains by conformational changes. This structural response can be induced by an additional dimerization and results in a covalent modification of intracellular side chains. The new conformation is then recognized by cytosolic partner molecules. In this connection GTP binding pro-... 

Recent advances in measuring the kinetics of the various electron-transfer steps in this system have been achieved by use of flash photolysis of ruthenated derivatives of cytochrome c (Ru-Cc) (17-19). In these studies [Ru(bpy)3]2+ is covalently bound to a surface residue at a site that does not interfere with the docking of cytochrome c to cytochrome c oxidase. Solutions are then prepared containing both Ru-Cc and cytochrome c oxidase, and the two proteins associate to form a 1 1 complex. Flash photolysis of the solution leads directly to the excitation of the RuII(bpy)3 site, which then reduces heme c very rapidly. This method thus provides a convenient means to observe the subsequent intracomplex electron transfer from heme c to cytochrome c oxidase and further stages in the process. 

Gehlhaar, D. K., Bouzida, D., Rejto, P. A. (1998) Fully automated and rapid flexible docking of inhibitors covalently bound to serine proteases. Proceedings of the 7th International Conference on Evolutionary Programming, MIT Press, Cambridge, MA., pp. 449-461. 

To the extent that they are covalently linked, the complex polyketide synthases are less reliant on association for function. In most systems, however, transient docking between multienzymes is required. Recently, it has been demonstrated that the regions of sequence upstream from N-terminal modules and downstream from C-terminal modules (referred to as interpolypeptide linkers) play a crucial role in the assembly of functional modules in vivo [78]. Clearly, the presence of such linkers will also be important for productive biosynthesis in vitro using multiprotein systems. 

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