Mexicana gapdh with nad bound hydrophobic groove fill

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Unformatted text preview: ill and Increase affinity Structure leads to “Targeted Combinatorial Chemistry” to fill the grooves optimally by adenosine derivatives Surface of L. mexicana* GAPDH with NAD bound. Hydrophobic Groove: Fill and Increase affinity AND selectivity Note: Leishmania mexicana GAPDH is ~77% sequence identical to Trypanosoma brucei GAPDH and all residues in the region of interest are identical in these two pathogenic “Trypanosomatids”. So these two enzymes are used interchangeably. Inhibition of L. mexicana GAPDH by Adenosine Derivatives Crystal structure of L. mexicana GAPDH with “NMDBA” Clearly visible is the selectivity cleft between Met39 and Val206* (from the neighboring monomer), with the dimethoxybenzamido group of NMDBA inserted into it. The surface has been color coded according to the electrostatic potential. Red represents negative potential and blue positive potential. “NMDBA”: A new inhibitor with 105-fold (!) affinity gain compared to the initial inhibitor adenosine. (You don’t need to know the chemical formula of NMDBA) Stephen Suresh Antonysami, Michael Gelb and coworkers, Wes Van Voorhis, Fred Buckner, Christophe Verlinde Useful Problems at end of Chapter 12, 3rd Ed VVP: 1, 5, 10, 14, 19, 25 Useful Problems at end of Chapter 12, 4th Ed VVP: 1, 11, 13, 19, 27 Useful Problems at end of Chapter 8, 7th Ed Stryer: 1, 5, 6, 14, 20a-c, 24 What you have to know about Enzyme Kinetics, Equations and Plots 0. You do not need to know the derivation of any equation, but you need to know: 1. Michaelis Menten Equations (For three cases: without inhibition, with competitive inhibition, and with uncompetitive inhibition as discussed on the slides). 2. The definitions of Ki and α for competitive inhibition, and of Ki’ uncompetitive inhibition. and α’ for 3. The Lineweaver-Burk equations. (For the same three cases as mentioned under point 1 above). 4. The definition of KM i.e. the Michaelis constant. 5. The Michaelis-Menten graph and the equations mentioned on the slide "Summary of special positions on the Michaelis Menten graph". 6. The Lineweaver-Burke plots for no inhibition, competitive inhibition and uncompetitive inhibition cases – including the equations for the slope of the lines in the case of competitive inhibition and for the point of intersection on the y-axis in the case of uncompetitive inhibition on the LB plots....
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