Rotamer Rally - Beat Hereditary Tyrosinemia

Your Goal

A mutant gene for FAH (blue) is causing Hereditary Tyrosinemia type 1! The Baker lab needs your help to design a protein (yellow) that can bind to the mutant DNA and destroy it, curing the disease. Find the side chain that fits neatly inside the hole (outlined by gray dots) without poking outside of it.

Hereditary Tyrosinemia type 1 (HT1) is a genetic disease that affects children. It creates a variety of problems with the liver due to a faulty gene for the enzyme fumarylacetoacetate hydrolase (FAH). Although a child may have one health copy of the gene and one mutant copy, they still get the disease. Our plan is to design a protein that can recognize the mutant gene and cut it. Then, the body can use the healthy copy to repair it, removing the mutation. These newly healthy liver cells should then be able to repopulate the liver and restore function. Although such gene therapy treatments are still unproven, if it works this approach could be used to target many other diseases too, such as Severe Combined Immunodeficiency Syndrome (SCIDS). Learn more about Hereditary Tyrosinemia from WebMD.

How to Play

• Choose an amino acid from the drop down list.
• Cycle through the choices for that amino acid by pressing the "Next" and "Previous" buttons.
• Your current choice is outlined in orange.
• When you think you've found a side chain that fits inside the hole, click and drag it around to make sure it isn't poking out.
• When you think you've got it, check your answer by clicking "Submit choice". (This doesn't do anything yet, but we're working on it!)
• You've defeated Hereditary Tyrosinemia!

When You're Done

• Download the full game and try more complicated problems.
• Learn more about the FAH gene and its role in Hereditary Tyrosinemia type 1.
• Learn about other diseases that the Baker lab is fighting through Rosetta@home.

The Hardest Version

You don't get much help here. All you can see is the outline of the pocket. You'll have to spot hydrogen bonds and steric clashes for yourself.

The Less-Hard Version

In addition to the outline of the pocket, you can see hydrogen bonds (green dots). You'll still have to avoid steric clashes for yourself.

The Easiest Version

Here you get the outline of the pocket, indicatiors for hydrogen bonds (green dots), and indicators of steric clashes (pink spikes). Try to find the best hydrogen bonds while avoiding any major clashes.

One More Variation

At the request of this structure's designer, this version also shows atom colors for the sidechains. Oxygens (red) and nitrogens (blue), together with their hydrogens (not shown), form hydrogen bonds. (You may notice this structure differs slightly from the ones above; it's a very slightly different design. Also, the protein is now peach and the DNA is now green.)