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MIT OpenCourseWare http://ocw.mit.edu 5.36 Biochemistry Laboratory Spring 2009 For information about citing these materials or our Terms of Use, visit: http://ocw.mit.edu/terms .
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Kinase Domains: Structure and Inhibition I. Conserved and variable features of kinase domains A. Structural similarities B. Active and inactive forms II. Abl and Bcr-Abl inhibition by Gleevec III. Gleevec resistance in Bcr-Abl mutants A. Direct interference with Gleevec binding B. Destabilization of the inactive form
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The catalytic domain (or kinase domain) of eukaryotic protein kinases is highly conserved both in sequence and structure Kinase activity requires binding of the peptide substrate (to be phosphorylated) and Mg-ATP to the catalytic domain.
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N -lobe Kinase domains have a bilobal structure composed of an N-lobe (amino lobe) that • contains a 5-stranded beta sheet and an alpha helix ( α C ).
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N -lobe Kinase domains have a bilobal structure composed of an N-lobe (amino lobe) that • contains a 5-stranded beta sheet and an alpha helix ( α C ). • comprises residues 225-350 of Abl (shown here). • contributes to ATP binding.
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N -lobe Kinase domains have a bilobal structure composed of an N-lobe (amino lobe) that • contains a 5-stranded beta sheet and an alpha helix ( α C ). • comprises residues 225-350 of Abl (shown here). • contributes to ATP binding.
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C -lobe Kinase domains have a bilobal structure composed of an N-lobe and a C-lobe (carboxy lobe) that • is made up of multiple alpha helices. • comprises residues 354-498 of Abl (the larger lobe). • is the location of peptide substrate binding.
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C -lobe Kinase domains have a bilobal structure composed of an N-lobe and a C-lobe (carboxy lobe) that • is made up of multiple alpha helices. • comprises residues 354-498 of Abl (the larger lobe). • is the location of peptide substrate binding.
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The hinge region (between the two lobes) contains several conserved residues that provide the catalytic machinery and make up an essential part of the ATP binding pocket. hinge region Among all kinases, Mg-ATP binding is primarily in the N -lobe and hinge region.
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(conserved residues in magenta) ATP Binding ( P ) loop • A ____-rich region in the N-lobe (typically a flexible loop between strands of the beta sheet or between the beta sheet and an alpha helix) that is highly conserved among kinases.
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Color scheme for atoms oxygen- red nitrogen- blue carbon- black, grey, or background color sulfur- yellow phosphorus- orange
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ATP Binding ( P ) loop A ____-rich region in the N-lobe (typically a flexible loop between (conserved residues in magenta) Gly strands of the beta sheet or between the beta sheet and an alpha helix) that is highly conserved among kinases. The backbone atoms of the conserved P-loop sequence, GXGXXG, interact with the non-transferred phosphate atoms of ATP.
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