Wednesday, June 11, 2014

Could LxxLL be a key to a New Site for Target Drugs?

We have mapped the entire human genome. We have discovered specific site targeting drugs that have been a huge success in killing cancer. What is next? Of course to further embark on this newly discovered path and target other genes for success! 

How do these targeting drugs work? Lets look at the human papillomavirus (HPV) vaccine. This vaccine is preventing strains 16 and 18 from infecting women.These strains are the cause of at least 70% of cervical cancer cases. When HPV infect someone, it acts as a retrovirus. It copies into human DNA. Then, it makes an E6 protein. This protein is not equivalent to the human one, but from HPV. This E6 protein floats around cells and attaches with ubiquitin ligase, a protein that degrades genes from doing their job. There is a domain on this E6 protein that start with Zinc C domain and terminates with a Zinc N domain. In between is a linker helix domain that is very hydrophobic. This makes up the LxxLL sequence with L being acidic Leucine and x being other hydrophobic amino acids. This hydrophobic pocket then binds with extreme ease to proteins like p53 and RB. When they are in contact, ubiquitin ligase then deregulates the protein E6 is bound to. In turn, this then causes no tumor suppression or cell death and cancer develops. Because HPV is sexually transmitted almost all of these cases result in cervical cancer. 

  Figure 1: E6 protein structure when bound with ubiquitin ligase.
The top image shows the structure of the folding of the E6 protein, in yellow is the first Zinc domain, in grey is the linker helix domain and in purple is the terminal Zinc domain. The bottom images shows the hydrophobic LxxLL pocket. 

A crucial point to notice in this process is that the LxxLL pocket can bind with a plethora of different proteins. Targeted therapies do just this. If we could make a drug/ structure that has a pocket like LxxLL that could go in and bind to proteins that are mutated, we could used this process to treat cancer. This is especially important because proteins like RB and p53 are in almost all cases of cancer and there has not been much research done on these oncoproteins. Targeting drugs have proven in the past to be very successful in curing targeted cancer. This specific pocket could be useful for further research in this field.

Even though this started with the HPV vaccine which does not cure cancer, it prevents it, if science found the technology to to build a protein that when inserted into a cancer cell could latch onto mutated proteins and regulate them again, we could help cure many forms of cancer. Evidence shows through the HPV that it really does work. Our next step is to instead of using it as a prevention, we use this technology as a cure. By knowing how HPV attacks proteins we can do the same with an artificial structure. If we went after proteins as common in mutations as p53 and RB we could change many lives. I would love to see further research on this LxxLL pocket. I feel that having a technology break through would come best with furthering our knowledge on targeting mutations on proteins that influence all cancers. This pocket could be the start of a new era in cancer research. 

Work Cited:

Zanier, K., S. Charbonnier, A. O. M. O. Sidi, A. G. Mcewen, M. G. Ferrario, P. Poussin-Courmontagne, V. Cura, N. Brimer, K. O. Babah, T. Ansari, I. Muller, R. H. Stote, J. Cavarelli, S. Vande Pol, and G. Trave. "Structural Basis for Hijacking of Cellular LxxLL Motifs by Papillomavirus E6 Oncoproteins." Science 339.6120 (2013): 694-98. Web. 12 May 2014. <>.