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Using the 3D Shape of Proteins to Design Drugs that Inhibit Protein Function
Before you start this activity, make sure you have the program Cn3D installed on your computer.
Protein Channels
Regulate movement of substances across the plasma membrane. E.g. The CFTR protein pumps ions across membranes
Transport
Haemoglobin (far right) in red blood cells transports oxygen to cells around the body
Source: http://www.biology.arizona.edu/biochemistry/tutorials/chemistry/page2.html http://www.cbp.pitt.edu/bradbury/projects.htm 2 http://www.abc.net.au/cgi-bin/common/printfriendly.pl?/science/news/enviro/EnviroRepublish_1191825.htm http://www.umass.edu/microbio/chime/
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Hydrogen peroxide
water
Enzyme proteins have specific sites where all the action happens. We call this the active site. Molecules that need to be ripped apart or put together enter the active site. Each protein has a specific shape so it will only perform a specific job.
Joining things together Ripping things apart
http://chsweb.lr.k12.nj.us/mstanley/outlines/enzymesap/Enzymesap.html 4 http://academic.brooklyn.cuny.edu/biology/bio4fv/page/active_.html
In the case of proteins, the monomers are amino acids. There are
20 different amino acids. AA
AA
AA
AA
AA AA
AA
Each protein molecule has a characteristic 3D shape that results from coiling and folding of the polymer chain.
Protein chains
Each protein has a specific sequence of amino acids that are linked together, forming a polypeptide
http://www.mywiseowl.com/articles/Image:Protein-primary-structure.png
Source: http://www.rothamsted.bbsrc.ac.uk/notebook/courses/guide/prot.htm#I
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The final protein may be made up of more than one polypeptide chain.
The polypeptide chains may be the same type or different types.
Source: http://fig.cox.miami.edu/~cmallery/150/chemistry/hemoglobin.jpg 11
MALTOSE
STARCH GLUCOSE
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Active Site
Pig
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Amylase in Cn3D
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Influenza Pandemics
The Spanish Flu in 1918, killed approximately 50 million people. It was caused by the H1N1 strain of influenza A.
The Asian Flu in 1957 was the H2N2 influenza A strain. Worldwide it is estimated that at least one million people died from this virus.
The Hong Kong Flu in 1968 evolved into H3N2. 750,000 people died of the virus worldwide
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Influenza epidemics
Economic Effects:
Days away from work Providing medical advise and treatment Mortalities Figure 1. Weekly number of influenza and pneumonia deaths per 10 000 000 population in the United States, France, and Australia (black line).
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(H)
(N)
N and H have special shapes to perform specific jobs for the virus. 17
Virus
N cuts the links between the viruses H attaches to cell surface and the cell surface so virus particles proteins so virus can enter cell are free to go and infect more cells. Proteins on cell surface
Your turn
Explore the research of an Australian team of scientists headed by Prof Peter Coleman. They designed the flu drug, Relenza.
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RELENZA
This link will open a Cn3D file of Neuraminidase with the drug relenza blocking its active site
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Venoms to drugs
Link to watch movie
A team of scientists from Melbourne University have patented a toxic chemical from the venom of an Australian Cone Shell.
The chemical, called ACV1, is an analgesic that will help relieve chronic pain. It is more powerful than morphine and is not addictive.
This analgesic will be used to treat pain resulting from nerve injury, post-surgical pain, phantom limb pain in amputees, leg ulcers in diabetics or the pain of terminal AIDS or cancer.
ACV1 treats pain by blocking the transmission of pain along our peripheral nervous system This drug could generate an annual profit of greater than1 billion dollars to the company that develops it!
Source: http://www.unimelb.edu.au/ExtRels/Media/02media/02july08.html
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Some facts
Calcium, sodium and potassium ions control essential functions inside cells: calcium, for example, helps regulate the contraction of muscle cells. Ion channels control the entry and exit of ions into and out of cells.
Some conotoxins act as analgesics, interacting with ion channel receptors in nerves so the ion channel cannot open. Blocking ion channels stops ions from entering a neighbouring nerve fibre. No electrical impulse is set off so the pain message is switched off! Phew!
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Sodium ion
Calcium ion Acetylcholine
++ - -
- ++
4. Acetylcholine binds with receptor proteins changing the shape of the ion channel. 1. impulse generated along axon sodium 5.Electrical This opens the sodium ion channel to letin sodium. ions (red) rush and ions (green) rushthe out 6. Sodium ionsin set offPotassium an electrical impulse along next nerve cell. 7. The pain message is working. To block pain we can try to target the ion channels.
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Acetylcholine at work
Below is an image of a section of a nerve cell cut open to reveal one of the Sodium Ion channels that studs its surface. Lets slice through an ion channel to show its 2 Acetylcholine inner workings..
molecules bind to Receptor binding protein on an ion channel. The shape of the ion channel protein changes so the Na+ gate opens.
Outside Cell
Inside Cell
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Some conotoxins block acetylcholine (nACh) receptors that stud the surface of neurons. Lets eplore this ion channel in Cn3D
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Your turn
Source: http://www.theage.com.au/news/creative--media/painkiller-comes-out-of-its-shell/2005/07/24/1122143728598.html