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Serine Proteases
Teaching Points
Enzymes are biological catalysts that accelerate the rate of a reaction without being
modified during the process. Several families of enzymes exist, each with a specific
function. For example, proteases are enzymes that catalyze the cleavage of peptide
bonds, which are the bonds that join amino acids together to form proteins. Serine
proteases are members of this protease family. These enzymes are named after the
reactive serine residue located in the active site that is essential for the function of the
enzyme.
The active site of serine proteases contains three critical amino acids: serine, histidine
and aspartate. These residues are often referred to as the “catalytic triad.” When the
linear sequence of amino acids folds into its tertiary structure, these three residues are
arranged in such a fashion that enables the sidechain of the serine residue to become
negatively charged through the loss of the hydrogen off the hydroxyl R group to
histidine. This nucleophile can then make an attack on the carbonyl group of the peptide
bond that is to be cleaved.
Included within this collection are three serine proteases: Chymotrypsin, Elastase and
Trypsin. Each of these enzymes plays an essential role in digestion. They are secreted
by the pancreas as inactive zymogens into the small intestine, where they become
active through proteolytic cleavage events. Each of these enzymes contains the
catalytic triad within its active site, but they differ with respect to their target cleavage
sites. The size and chemical nature of the active sites of these enzymes accommodate
different substrates. Chymotrypsin cleaves peptide bonds that are next to aromatic
residues (phenylalanine, tyrosine or tryptophan). Trypsin cleaves next to basic residues
(lysine or arginine). Elastase is less discriminating, but prefers to cleave bonds near
small hydrophobic residues (alanine). The structure of the active site allows for these
specific cleavage sites to be positioned near the catalytic triad so that the active serine
residue can make the nucleophilic attack on the bond in order to cleave it.
This collection includes two versions of each of the enzymes: an α-carbon backbone
and a spacefill model. The α-carbon backbone models allow for students to compare
the three enzymes on different aspects, including secondary and tertiary structures and
characteristics of the active site. The spacefill version of the model allows the student to
appreciate how the different sidechains of each amino acid can interact to form the
protein. This model is colored using the David Goodsell color scheme that highlights
charged residues within the protein structure.
Models in this Collection
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α-carbon backbone models
o Chymotrypsin
o Elastase
o Trypsin
Spacefill models
o Chymotrypsin
o Elastase
o Trypsin
Model Details
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α-carbon backbone models
o Backbone format
o Color scheme
ƒ α-helices – red
ƒ β-sheets – yellow
ƒ Loops – grey
ƒ N terminus – green
ƒ C terminus – cyan
o Active site residues (His, Asp, Ser) in ball and stick and in CPK colors
(carbon is gray, oxygen is red and nitrogen is blue)
o Chymotrypsin
ƒ Derived from PDB file 4cha
ƒ Model made of plaster with the ZCorp printer
o Elastase
ƒ Derived from PDB file 4est
ƒ Model made of plaster with the ZCorp printer
o Trypsin
ƒ Derived from PDB file 4ptc
ƒ Model made of plaster with the ZCorp printer
Spacefill models
o Spacefill format
o Color scheme is developed by David Goodsell
ƒ Oxygen
• If neutral, colored pink
• If charged, colored bright red
ƒ Nitrogen
• If neutral, colored light blue
• If charged, colored bright blue
ƒ Carbon: white
ƒ Sulfur: yellow
Hydrogen atoms are colored the same color as the atom to which
each is attached
o Chymotrypsin
ƒ Derived from PDB file 4cha
ƒ Model made of plaster with the ZCorp printer
o Elastase
ƒ Derived from PDB file 4est
ƒ Model made of plaster with the ZCorp printer
o Trypsin
ƒ Derived from PDB file 4ptc
ƒ Model made of plaster with the ZCorp printer
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Documentation included
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Teaching points and inventory
How do the models fit back in the suitcase?
Enzyme Active Sites and Guide for Exploration
Serine Proteases Teaching Exercises
Serine Proteases – distinguishing the models
Images of Serine Proteases
Resources
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Animation: Nucleophilic Attack of Serine
o http://www.andrew.cmu.edu/course/03-231/Protease/SerPro.htm
o This website provides an animated view of the mechanism of action that
serine proteases use in order to catalyze the hydrolysis of the peptide
bond.
Chime tutorial of the active site of serine protease:
o http://www.biochem.arizona.edu/classes/bioc462/462a/NOTES/ENZYMES
/serprot.html
Superimposition of three serine proteases in Chime:
o http://www.andrew.cmu.edu/course/03-231/ProtStruc/3TCE.htm
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