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Today Lecture about kinases Formation of project groups Discussion about project content.

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1 Today Lecture about kinases Formation of project groups Discussion about project content

2 Protein kinases Before we describe how protein kinases work, first an interlude dealing with the representation of protein structure

3 Proteins are made of a chain (or chains) of covalently bound amino acids

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5 5 The -N-C-C-N-C-C- acts as the main chain or « backbone » the atom groups that define the type of amino acid form the « side chains » Backbone representation

6 The string of amino acids folds either in the form of a helix, a  -strand or as a non-structured loop (not shown)

7 An example of a short polypeptide comprising  -helices,  - sheets and loops loop  -helix  -sheet

8 The amino acid sequence of a protein kinase >P06213| (=275 amino acids)...ITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKGFT CHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMAAE IADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRW MAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDNCP ERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSF…

9 The folded string of the amino acids that constitute a protein kinase can be represented in different ways Show all atoms of the amino acid in a stick representation Show all atoms of the amino acid in a sphere representation Show the surface of the protein Show only the back-bone of the amino acid in a ribbon representation

10 Phosphorylation and dephosphorylation : protein kinases and protein phosphatases

11 Protein kinases What do they do? What do they look like? How do they do it?

12 This is what they do

13 Understanding enzymes as nano- machines; ATP is nicely buried inside the protein kinase whereas the substrate (only a short peptide shown in blue) is fixed onto the surface of the protein The tyrosine residue, shown in green, is perfectly positioned to receive the  -phosphate ATP tyrosine containing substrate This is what they look like

14 Understanding enzymes as nano-machines; Protein kinases have two lobes, the upper one is the N-terminal lobe, the bottom one the C-terminal lobe. the catalytic cleft sits at the interface between the two; the catalytic residue (not shown) as well as ATP reside in the cleft (ready for action) N-terminal lobe C-terminal lobe catalytic cleft ATP This is what they look like

15 Understanding enzymes as nano-machines; A ribbon representation illustrating the position of highly conserved amino acids As their level of conservation indicates, these amino acids are vital for the functioning of the protein kinase They control the position of ATP (lys, asp, glu), substrate (blue ribbon) and the transfer of electrons (asp*) leading to hydrolysis of ATP *

16 And this is how they do it (understanding enzymes as nano-machines)

17 serine/threonine versus tyrosine protein kinases

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19 Certain protein kinases are multidomain enzymes

20 Kinases exist in an incompetent state and require activation before they can phosphorylate substrate

21 Different modes of activation of protein kinases

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