T. Mann

Bio: T. Mann is an academic researcher. The author has an hindex of 1, co-authored 1 publications receiving 625 citations.

Advances in Enzymology

Abstract: Advances in Enzymology and Related Subjects of Biochemistry Vol 24 Edited by F F Nord Pp v + 572 (New York and London: Interscience Publishers, a Division of John Wiley and Sons, 1962) 120s

A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib): Relationships among Protein Conformation, Inhibitor Off-Rate, and Receptor Activity in Tumor Cells

Abstract: GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.

Atmospheric Dimethyl Sulphide and the Natural Sulphur Cycle

Abstract: ALL models of natural processes for the transfer of sulphur on a global scale1–4 require some volatile or gaseous sulphur compound to complete the cycle by providing a vehicle for the transfer of sulphur from the sea through the air to the land surfaces. In the past, this role has been assigned to H2S and an average atmospheric concentration of 2×10−10 by volume satisfied the mass transfer needs of the models. Attempts to detect the presence of these concentrations of H2S have always failed and, more important, the ocean surface waters are much too oxidizing to permit the existence of H2S at concentrations sufficient to sustain an atmospheric equilibrium concentration of 2×10−10 by volume. Many elements form volatile methyl derivatives; Challenger5 reported that many living systems produced dimethyl sulphide (DMS), and that prominent among them were marine algae. Here we suggest that DMS is the natural sulphur compound which fills the role originally assigned to H2S; that of transferring sulphur from the seas through the air to land surfaces.

Structure of nitric oxide synthase oxygenase dimer with pterin and substrate.

Abstract: Crystal structures of the murine cytokine-inducible nitric oxide synthase oxygenase dimer with active-center water molecules, the substrate l-arginine (l-Arg), or product analog thiocitrulline reveal how dimerization, cofactor tetrahydrobiopterin, and l-Arg binding complete the catalytic center for synthesis of the essential biological signal and cytotoxin nitric oxide. Pterin binding refolds the central interface region, recruits new structural elements, creates a 30 angstrom deep active-center channel, and causes a 35° helical tilt to expose a heme edge and the adjacent residue tryptophan-366 for likely reductase domain interactions and caveolin inhibition. Heme propionate interactions with pterin and l-Arg suggest that pterin has electronic influences on heme-bound oxygen. l-Arginine binds to glutamic acid–371 and stacks with heme in an otherwise hydrophobic pocket to aid activation of heme-bound oxygen by direct proton donation and thereby differentiate the two chemical steps of nitric oxide synthesis.