Navigation Links
Scripps Research study challenges conventional theory of modern drug design
Date:10/10/2010

JUPITER, Fl, October 7, 2010 Scientists from The Scripps Research Institute have uncovered new evidence that challenges the current theory about a process key to the way modern drugs are designed and how they work in the human body.

The new study was published October 10, 2010 in an advance, online edition of the journal Nature Chemical Biology.

Currently, the theory about ligands compounds that bind to proteins and trigger a specific biological action and how they bind to proteins runs along the lines of a one person-one vote paradigm. Ligands are considered to be the relatively static partner in the process, and easily rejected if the protein dramatically changes shape.

In contrast, working with the molecular systems that recognize the hormone estrogen, the new Scripps Research study found that as protein receptors change shape ligands can adapt to that change, binding productively to both active and inactive structures.

"To our great surprise, the ligand bound differently to the active and inactive conformations of the receptor," said Kendall Nettles, an associate professor in the Department of Cancer Biology at Scripps Florida. "This strongly suggests a novel mechanism for managing [cell] signaling activity. The implications of this are profound, both for our understanding of how ligands regulate protein activity, and as a novel approach in drug discovery."

Changing the Drug Discovery Model

In the current study, the scientists worked with a receptor (which binds substances triggering certain biological effects) for the hormone estrogen and a well known estrogen receptor antagonist (which blocks the receptor). Estrogen receptors are activated by the hormone estrogen, which is one of two primary female sex hormones (the other is progesterone). Disturbances in estrogen levels play a role in number of disorders including cancers, heart disease, and stroke in women.

When ligands bind to a specific subset of receptors, the ligands stabilize specific protein conformations, turning on (or off) molecular switches that control diverse cellular functions. For example, the binding of the breast cancer treatment tamoxifen is specific for the inactive conformation of the estrogen receptor this locks the receptor in place, blocks the active conformation and prevents tumor growth.

"Our new findings suggest that we need to think not only about an ensemble of protein conformations, but also an ensemble of ligand binding orientations when we think about therapeutic compounds," Nettles said. "As the protein and ligand move together, each can have a unique affinity, and activity profile, which working together defines the signaling output."

Nettles is excited by the possibility the new study suggests of working with an ensemble of ligand conformations, perhaps combining one with anti-inflammatory properties which play a role in cancer with another that blocks tumor growth. "This would give you dual therapeutic activity, potentially doubling the effectiveness of the treatment," he said.

Nettles is also eager to find out whether the new study's findings apply to other ligand-protein pairs. "If ligand dynamics turn out to be a general feature of small molecule signaling," he said, "then our findings have the potential to transform how we think about chemical biology."


'/>"/>

Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert

Related biology news :

1. Scripps research team solves structure of beneficial virus
2. Scripps research team sheds light on immune system suppression
3. Scripps Florida scientists awarded $1.5M to fight major water and food parasites
4. Scripps research scientists identify compounds for stem-cell production from adult cells
5. Scripps research scientists identify blood component that turns bacteria virulent
6. Scripps research team defines new painkilling chemical pathway
7. Dolphin population stunted by fishing activities, Scripps/NOAA study finds
8. Scripps Research scientists shed light on how DNA is unwound so that its code can be read
9. Scripps scientists develop first examples of RNA that replicates itself indefinitely
10. Scripps scientists create first crystal structure of an intermediate particle in virus assembly
11. Historical photographs expose decline in Floridas reef fish, new Scripps study finds
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/2/2016)... 2, 2016 The Department of Transport ... the 44 million US Dollar project, for the , ... including Personalization, Enrolment, and IT Infrastructure , to ... production and implementation of Identity Management Solutions. Numerous renowned international ... Decatur was selected for the most compliant ...
(Date:5/20/2016)... , May 20, 2016  VoiceIt is excited ... with VoicePass. By working together, VoiceIt ...  Because VoiceIt and VoicePass take slightly different approaches ... increases both security and usability. ... about this new partnership. "This marketing ...
(Date:4/28/2016)... BANGALORE, India , April 28, 2016 ... subsidiary of Infosys (NYSE: INFY ), and Samsung ... global partnership that will provide end customers with a ... and payment services.      (Logo: http://photos.prnewswire.com/prnh/20130122/589162 ... for financial services, but it also plays a fundamental part ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... ... June 27, 2016 , ... Rolf K. Hoffmann, former ... of the University of North Carolina Kenan-Flagler Business School effective June ... UNC Kenan-Flagler, with a focus on the school’s international efforts, leading classes and ...
(Date:6/24/2016)... , June 24, 2016 Epic Sciences ... detects cancers susceptible to PARP inhibitors by targeting ... cells (CTCs). The new test has already been ... in multiple cancer types. Over 230 ... damage response pathways, including PARP, ATM, ATR, DNA-PK ...
(Date:6/23/2016)... Wausau, WI (PRWEB) , ... June 23, 2016 ... ... probiotic supplements, is pleased to announce the launch of their brand, UP4™ Probiotics, ... supplements for over 35 years, is proud to add Target to its list ...
(Date:6/23/2016)... , June 23, 2016 Houston ... with the Cy-Fair Sports Association to serve as ... the agreement, Houston Methodist Willowbrook will provide sponsorship ... and connectivity with association coaches, volunteers, athletes and ... with the Cy-Fair Sports Association and to bring ...
Breaking Biology Technology: