Inhibition structural basis

It is not clear why some organisms have two 14-3-3 isoforms while others have up to 12. Binding 14-3-3 inhibits the plant enzyme nitrate reductase and there appears to be no selectivity between plant 14-3-3 isoforms in fact yeast and human isoforms appear to work equally as well in vitro. The best example where selectivity has been demonstrated is human 14-3-3o. 14-3-3o Preferential homodimerizes with itself and crystallization revealed a structural basis for this isoform s dimerization properties as well as for its specific selectivity for target binding proteins. Here partner specificity is the result of amino acid differences outside of the phosphopeptide-binding cleft. 

The concept that different ligands play an active role in ER function is apparent at the biochemical level. In addition to competitive inhibition of estrogen binding, antiestrogens induce unique conformations/stiuctures of both ERa and ER 3. This provides a structural basis for the unique biological activities displayed by the different compounds [1]. 

D. Gildehaus, J. M. Miyashiro, T. D. Penning, K. Seibert, P. C. Isakson, and W. C. Stallings, Structural basis for selective inhibition of cyclooxygenase-2 by antiinflammatory agents, Nature 384 644 (1996). 

Roe, S.M., Prodromou, C., O Brien, R., Ladbury, J.E., Piper, P.W. and Pearl, L.H. (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumour antibiotics radicicol and geldanamycin. Journal of Medicinal Chemistry, 42, 260-266. 

Pak, J.Y. Gildehaus, D., Miyashiro, J.M., Penning, T.D., Seibert, K., Isakson, P.C., and Stallings, W.C. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature... 

Winchester BG Cenci di Bello I, Richardson AC, Nash, RJ, Fellows LE, Ramsden NG Fleet G. (1990) The structural basis of the inhibition of human glycosidases by castanospermine analogues. Biochem J 269 227-231. 

Asano N, Oseki K, Kizu H, Matsui K. (1994) Nitrogen-in-the-ring pyra-noses and furanoses Structural basis of inhibition of mammalian glycosidases. J Med Chem 37 3701-3706. 

Khalid A, Azim MK, Parveen S, et al. Structural basis of acetylchoflnesterase inhibition by triterpenoidal alkaloids, Biochem Biophys Res Commun 331 1528— 1532, 2005. 

Sanders, B.D., Zhao, K., Slama, J.T and Marmorstein, R. (2007) Structural basis for nicotinamide inhibition and base exchange in Sir2 enzymes. Molecular Cell, 25 (3), 463 72. 

Halpert, J. R. (1995) Structural basis of selective cytochrome P450 inhibition. Annu. Rev. Pharmacol. Toxicol. 35, 29-53. 

F. Vallee, K. Karaveg, A. Herscovics, K. W. Moremen, and P. L. Howell, Structural basis for catalysis and inhibition of /V-glycan processing class I a-l,2-mannosidases, J. Biol. Chem., 275 (2000) 41287-41298. 

M.R. Groves, Z.J. Yao, P.P. Roller, T.R. Burke Jr, D. Barford, Structural basis for inhibition of the protein tyrosine phosphatase IB by phosphotyrosine peptide mimetics. Biochemistry 37 (1998) 17773-17783. 

Russo, A.A., Tong, L., Lee, J.O., Jeffrey, P.D. and Pavletich, N.P. Structural basis for inhibition of the cychn-dependent kinase Cdk6 by the tumour suppressor pl6INK4a (1998) Nature 395, 237-243... 

Roe SM, Prodromou C, O Brien R, Ladbury JE, Piper PW, Pearl LH (1999) Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin. J Med Chem 42 260... 

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