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Product. Reactant. Energy Landscape. Eco RV. Phosphodiester hydrolysis. H 2 O. “Reactant State” Crystal Structure. Ala 92 (Mutated from Lys). Cleavage Site. 3.7Å. Water Oxygen. Molecular Dynamics of Wild Type. PETRA IMHOF. Lys 92. Water Molecule.
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Product Reactant Energy Landscape
“Reactant State” Crystal Structure Ala 92 (Mutated from Lys) Cleavage Site 3.7Å Water Oxygen
Molecular Dynamics of Wild Type PETRA IMHOF Lys 92 Water Molecule
Molecular Dynamics of Wild Type PETRA IMHOF MD I
Principal Component Principal Components I
Molecular Dynamics of Wild-Type Deprotonated Lys 92 Water Molecule
Muscle Contraction Thin filament Thick filament
SONJA SCHWARZL ATP Hydrolysis by Myosin
SerineProtease Melanie Böttcher
Index • Definition • Digestive enzymes • Blood clotting • Complement system
Serine Protease • Cutting of certain peptide bonds in other proteins • Activity depends on a set of amino acid residues in the active site of the enzyme • Based on nucleophilic attack of the targeted peptidic bond by a serine
Serine • Amino acid • alcohol as residue
Digestive enzymes Chymotrypsin • Chymotrypsin, Trypsin, Elastase • closely-similar structures • different substrate specificities • Pancreatic proteases proenzymes trypsinogen and chymotrypsinogen synthesized in the pancreas and secreted into the lumen of the small intestine Elastase Trypsin
Trypsinogen-Trypsin • loss of six amino acids from one end • overall structures remain similar • Ca++ for thermal stability activated enzyme does have more of its structure organized into sheets
Trypsin • Trypsin cleaves peptide bonds on the C-terminal side of arginines and lysines Alcaline amino acids • Activation by enteropeptidase or through protoelyse • Optimum pH 7 to 8
Chymotrypsinogen-Chymotrypsin • Chain is clipped in four places release of 2 dipeptides creation of two breaks in the backbone • 1-13 segment retained as part of the active enzyme, linked on by a disulfide bond Activation by trypsin
Chymotrypsin • Active site: His57-Ser195-Asp102 • Chymotrypsin cuts on the C-terminal side of tyrosine, phenylalanine, and tryptophan residues • hydrolysis of bonds of leucyl, methionyl, asparaginyl and glutamyl residues.
Elastase • cuts peptide bonds next to small, uncharged side chains such as those of alanine, serine, valine and threonin • cuts collagen
Blood Clotting System • Cascade of several mechanism • Involved Serine Proteases • Thrombin • Plasmin • Factor 10 a • Factor 11 b
Human Thrombin with the Amino acids 55-65 of Hirudin Thrombin • Inactivated Prothrombin cleaves into activated Thrombin • Thrombins cuts Paraglobuline (= fibrinoplastic substance) and forms the soluble state of it • Precipitation by plasmasalt in unsoluble state
Serpins • Serine Protease Inhibitors • inhibit the action of their respective serine protease serine protease binds the serpin instead of its normal substrate protease makes a cut in the serpin leading to • the formation of a covalent bond linking the two molecules • a massive allosteric change in the tertiary structure of the serpin which moves the attached protease to a site where it can be destroyed
Occurrence/ Function • stop proteolytic activity • blood plasma • clotting • complement systems where a tiny initial activating event leads to a rapidly amplifying cascade of activity
Serpin Deficiencies • inherited diseases • mutation in the encoding gene for serpin • examples
Alpha-1-Antitrypsin • Serpin for Elastase • secreted by neutrophils (lung infection) • emphysema • liver damage • tests are running
The Others • Other Serine Proteases • Subtilisin • Acetylcholinesterase • Serpinlike Molecules • Angiotensinogen • Chicken Ovalbumin