Featured Research

from universities, journals, and other organizations

Protein 'Key' Could Aid Search For Cancer Drugs

Date:
December 16, 2004
Source:
Rice University
Summary:
New research at Rice University is allowing biochemists to understand a key hierarchy of protein interactions that occurs in DNA replication, showing for the first time how a key protein "trumps" its rivals and shuts down cell division while DNA repairs take place.

HOUSTON, Dec. 7, 2004 -- New research at Rice University is allowing biochemists to understand a key hierarchy of protein interactions that occurs in DNA replication, showing for the first time how a key protein "trumps" its rivals and shuts down cell division while DNA repairs take place.

The work, sponsored by the American Cancer Society, appears in the Dec. 8 issue of the journal Structure. It could aid drug makers in designing targeted therapies that block cancer cells from multiplying.

"All cancers are marked by some form of DNA replication gone awry, so a basic understanding of DNA replication is of paramount importance to those designing cancer-fighting drugs," said lead author Yousif Shamoo, assistant professor of biochemistry and cell biology. "In addition, almost every form of life – including bacteria – use a variant of the protein that we studied, and we believe the work may also aid drug makers who are developing new forms of antibiotics."

In the study, Shamoo and graduate student John Bruning used x-ray crystallography and isothermal titration calorimetry to determine the structures of two variants of a protein called Human Proliferating Cellular Nuclear Antigen, or PCNA.

PCNA is a member of the "sliding clamp" family of proteins, which are so-named because of their unique shape and function. Sliding clamps are ring-shaped proteins that slide along strands of DNA. DNA is fed through the hole in the center, and the PCNA acts as a docking mechanism for other proteins that need to interact with the DNA to make repairs or copies or to take part in other genetically regulated tasks. Genes that code for sliding clamp proteins are present in all forms of life except for some viruses.

In humans, at least a dozen proteins are known to dock with PCNA. Each of them docks with PCNA by inserting a kind of key known as a PCNA-interacting protein, or "PIP-box," which binds chemically to the PCNA and holds the docked protein on the DNA strand.

"Each protein that binds with PCNA has its own version of the key, but all the keys fit into the same lock," said Shamoo. "There is a hierarchy among the PIP-box proteins, with some winning out and trumping others before they get a chance to bind. By deciphering the structure of two of these keys, while they were in the lock, we were able to determine their binding energies and find out how the strongest key -- the trump card -- blocks the others and shuts down DNA replication."

The structure of PCNA containing the trump key, the PIP-box from a cell regulatory protein called p21, was solved by researchers at the Rockefeller University. P21 is important because it is produced by cells with damaged DNA. In healthy cells, p21 binds strongly with PCNA to prevent the cells from making copies of DNA until the genetic damage is repaired.

Shamoo and Bruning solved the structure of PCNA containing two other forms of PIP-box keys, both of which are involved in DNA replication. By comparing the chemical structure of the weaker keys against the stronger p21 key, they were able to determine how p21 optimizes its connection to PCNA.

If drug makers can replicate p21's strategy in targeted cancer-fighting compounds, they could attack cancer cells' ability to reproduce at the most basic level.

"The sliding clamp protein that's used by bacteria has the same function as PCNA in humans, but the keys for bacteria are very different from those in humans," said Bruning. "If bacteria use a similar hierarchy to access to their PCNA, it might be possible to design an antibiotic that plays the bacterial trump card without affecting human cells at all."

###

The research was funded by the American Cancer Society, the Welch Foundation and the Houston Area Molecular Biophysics Program.


Story Source:

The above story is based on materials provided by Rice University. Note: Materials may be edited for content and length.


Cite This Page:

Rice University. "Protein 'Key' Could Aid Search For Cancer Drugs." ScienceDaily. ScienceDaily, 16 December 2004. <www.sciencedaily.com/releases/2004/12/041208083014.htm>.
Rice University. (2004, December 16). Protein 'Key' Could Aid Search For Cancer Drugs. ScienceDaily. Retrieved August 1, 2014 from www.sciencedaily.com/releases/2004/12/041208083014.htm
Rice University. "Protein 'Key' Could Aid Search For Cancer Drugs." ScienceDaily. www.sciencedaily.com/releases/2004/12/041208083014.htm (accessed August 1, 2014).

Share This




More Health & Medicine News

Friday, August 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

House Republicans Vote to Sue Obama Over Healthcare Law

House Republicans Vote to Sue Obama Over Healthcare Law

Reuters - US Online Video (July 31, 2014) The Republican-led House of Representatives votes to sue President Obama, accusing him of overstepping his executive authority in making changes to the Affordable Care Act. Mana Rabiee reports. Video provided by Reuters
Powered by NewsLook.com
Despite Health Questions, E-Cigs Are Beneficial: Study

Despite Health Questions, E-Cigs Are Beneficial: Study

Newsy (July 31, 2014) Citing 81 previous studies, new research out of London suggests the benefits of smoking e-cigarettes instead of regular ones outweighs the risks. Video provided by Newsy
Powered by NewsLook.com
Dangerous Bacteria Kills One in Florida

Dangerous Bacteria Kills One in Florida

AP (July 31, 2014) Sarasota County, Florida health officials have issued a warning against eating raw oysters and exposing open wounds to coastal and inland waters after a dangerous bacteria killed one person and made another sick. (July 31) Video provided by AP
Powered by NewsLook.com
Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins