Navigation Links
Could new discovery about a shape-shifting protein lead to a mighty 'morpheein' bacteria fighter?
Date:6/20/2008

A small molecule that locks an essential enzyme in an inactive form could one day form the basis of a new class of unbeatable, species-specific antibiotics, according to researchers at Fox Chase Cancer Center.

Their findings, highlighted on the cover of the June 23 issue of the journal Chemistry & Biology, take advantage of an emerging body of science regarding "morpheeins" proteins made from individual components that are capable of spontaneously reconfiguring themselves into different shapes within living cells.

The researchers discovered a small molecule, which they have named morphlock-1, binds the inactive form of a protein known as porphobilinogen synthase (PBGS), an enzyme used by nearly all forms of cellular life. The functioning form of PBGS is built from eight identical component parts in what is called an octamer configuration and is essential among nearly all forms of life in the processes that enable cells to use energy. The other configuration is made of six parts or a hexamer configuration and serves as a "standby" mode for the protein.

"As the name suggests, morphlock-1 essentially locks the hexamer configuration into place, preventing its protein subunits from reconfiguring into the active assembly," says lead investigator Eileen Jaffe, Ph.D, a Senior Member of Fox Chase. "Targeting morpheeins in their inactive assemblies provides an entirely new approach to drug discovery."

While their study was performed using a pea plant-version of PBGS, the researchers have reason to believe the principle could apply to bacterial versions of PBGS as well. "Using morphlock-1 as a base, we are seeking to fine tune the molecule so that it blocks just the bacterial version of the PBGS enzyme, " Jaffe says.

"Because PBGS is so crucial for life, the part of the enzyme where chemistry happens is highly conserved through evolution," Jaffe says, meaning that an all-around PBGS-inhibiting drug would harm bacteria, peas and people alike. The area where the potential drug binds to the hexamer form of the protein, however, has been found to differ among species, depending how far the organisms have evolved from each other.

When PBGS is in its inactive hexamer form, there is a small cavity on the surface of the assembled complex. Using computer docking techniques, Jaffe and her Fox Chase colleagues identified a suite of small molecules predicted to bind to this cavity.

The researchers then bought and tested a selection of these molecules in the lab to see if any of them stabilized the pea PBGS in its hexamer assembly. One inhibitor in particular, given the name morphlock-1, potently drove the formation of the hexamer in pea PBGS, but not in that of humans, fruit flies, or the infectious bacteria Pseudomonas aeruginosa, or Vibrio cholerae, the latter of which causes cholera. Morphlock-1 is a potent inhibitor of pea PBGS, but not of the PBGS from these other organisms.

Jaffe coined the term "morpheein" in 2005 after a study of the structure of PBGS revealed its shape-shifting tendencies. While initially met with skepticism because the existence of morpheeins contradicts some classic concepts about protein structure and function, subsequent studies have reinforced that PBGS (and perhaps other proteins) exhibits this behavior. According to Jaffe, this study is the first to make use of alternate morpheein shapes as a potential strategy for drug discovery, in general, particularly for antibiotics.

"Multi-drug resistance drives the need for developing new antibiotics," Jaffe says. "Since drugs that stabilize the inactive PBGS hexamer need not be chemically similar to each other, it will be difficult for the bacterium to develop complete resistance to a cocktail of such compounds."


'/>"/>

Contact: Greg Lester
gregory.lester@fccc.edu
215-728-2753
Fox Chase Cancer Center
Source:Eurekalert  

Related medicine news :

1. Study provides hope that some transplant patients could live free of antirejection drugs
2. Study provides hope that some transplant patients could live free of anti-rejection drugs
3. HIV denialists spread misinformation online -- consequences could be deadly; and more
4. Virus Could Help Drive Obesity
5. Discovery of sugar sensor in intestine could benefit diabetes
6. Cranberry Could Juice Up Ovarian Cancer Treatment
7. Treating Diabetes During Pregnancy Could Lead to Thinner Kids
8. High-risk behaviors could lead to HIV epidemic in Afghanistan
9. Chinas 1-child policy could backfire on its elderly
10. 1.5 million children could be saved
11. FDA Seeks to Regulate Complementary and Alternative Medicine; Products Such as Vegetable Juice Could Be Restricted for Medical Use
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Could new discovery about a shape-shifting protein lead to a mighty 'morpheein' bacteria fighter?
(Date:6/25/2016)... ... ... "With 30 hand-drawn hand gesture animations, FCPX users can easily customize each ... Film Studios. , ProHand Cartoon’s package transforms over 1,300 hand-drawn pictures into hand ... select a ProHand generator and drag it above media or text in the Final ...
(Date:6/25/2016)... ... June 25, 2016 , ... On Friday, June 10, Van Mitchell, Secretary ... Work award to iHire in recognition of their exemplary accomplishments in worksite health promotion. ... Maryland Workplace Health & Wellness Symposium at the BWI Marriott in Linthicum Heights. iHire ...
(Date:6/24/2016)... (PRWEB) , ... June 24, 2016 , ... June 19, ... the dangers associated with chronic pain and the benefits of holistic treatments, Serenity ... who are suffering with Sickle Cell Disease. , Sickle Cell Disease (SCD) is a ...
(Date:6/24/2016)... ... June 24, 2016 , ... Dr. Amanda ... orthodontic treatment. Dr. Cheng has extensive experience with all areas of orthodontics, including ... accelerated osteogenic orthodontics. , Micro-osteoperforation is a revolutionary adjunct to orthodontic treatment. ...
(Date:6/24/2016)... Norcross, Georgia (PRWEB) , ... June 24, 2016 ... ... Year” awards today at the Clinical Decision Making in Emergency Medicine conference in ... who have authored journal articles published in Emergency Medicine Practice and ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... June 23, 2016 Roche (SIX: RO, ROG; ... for its Elecsys BRAHMS PCT (procalcitonin) assay as a ... septic shock. With this clearance, Roche is the first ... integrated solution for sepsis risk assessment and management. ... infection and PCT levels in blood can aid clinicians ...
(Date:6/23/2016)... 23, 2016 Research and Markets has ... 52" report to their offering. ... creates a favourable commercial environment for MedImmune to enter. The ... that will serve to drive considerable growth for effective anti-influenza ... to cap sales considerably, but development is still in its ...
(Date:6/23/2016)... INDIANAPOLIS , June 23, 2016 If ... Leaders Scholarship is any indication, the future is in ... at www.diabetesscholars.org by the Diabetes Scholars Foundation ... the way of academic and community service excellence. ... since 2012, and continues to advocate for people with ...
Breaking Medicine Technology: