Developing Oriented Circular Dichroism Spectroscopy as a Methodological Tool for Characterising Membrane Proteins

Lead Research Organisation: Birkbeck, University of London
Department Name: Biological Sciences

Abstract

Membrane proteins are physiologically-important molecules that are embedded in the phospholipid bilayers surrounding cells. They are the targets of a large number of pharmaceutical drugs because many of them, when mutated, are the causes of diseases. Most methods for examining membrane proteins require that the membranes that surround the proteins be dissolved by detergents, which removes interactions both with each other and with the surrounding lipids that may be important to their functioning. This proposal is to develop a methodological tool that will enable us to examine proteins in intact membranes, thereby preserving their native structure. The method, Oriented Circular Dichroism spectroscopy, would enable the examination of both their local structure and the changes in their structure and orientation associated with how they work.

Technical Summary

This is a proposal to develop a methodological tool, oriented circular dichroism spectroscopy, for examining the structure of membrane proteins embedded in phospholipid bilayers and/or 2-dimensional crystals. It would enable the analysis of protein secondary structure and orientation and, importantly, the monitoring of changes in these upon drug and ligand binding, as a means of investigating the dynamic nature and functioning of this class of proteins.

Planned Impact

The proposed methodological tool will have potential as a resource for the examination of membrane proteins embedded in phospholipid bilayers, and as a means for examining effects of ligand and drug binding to this class of proteins that play important roles in human health. Whilst this will primarily be a basic science tool, it has potential for application in the pharmaceutical industry as membrane proteins comprise a significant proportion of current drug targets. We have established contracts with a number of companies (pharmaceutical, chemical and SMEs) who access our Dichroweb analysis tool, which demonstrates that CD is a not only a methodology of interest to industry, but one they regularly use; indeed our Dichroweb tool was cited as a high impact case study in the 2007 RCUK Report on the Economic Impact of the Research Councils.
 
Description contributed to method development for oriented CD
Exploitation Route used by CASE student and analysis server used by other groups
Sectors Pharmaceuticals and Medical Biotechnology

URL http://anglerfish.cryst.bbk.ac.uk/
 
Description MRC CASE studentship
Amount £21,200 (GBP)
Organisation Pfizer Ltd 
Department Neusentis Pfizer
Sector Private
Country United Kingdom
Start 09/2013 
End 09/2017
 
Title PCDDB 
Description data bank for validated circular dichroism spectra 
Type Of Material Improvements to research infrastructure 
Year Produced 2014 
Provided To Others? Yes  
Impact more than 500,000 downloads already 
URL http://pcddb.cryst.bbk.ac.uk
 
Title new software tools for CD analyses 
Description software and websites and you tube videos about new infrastructure tools developed for CD spectroscopy and structural biology 
Type Of Material Improvements to research infrastructure 
Year Produced 2018 
Provided To Others? Yes  
Impact ongoing development of many new tools for bioinformatics and structural biology resources widespread usage of tools both in the UK and internationally 
 
Title oriented circular dichroism spectroscopy - methods development and software analysis tools 
Description development of methodology and software analysis tools for oriented CD spectroscopy 
Type Of Material Improvements to research infrastructure 
Year Produced 2017 
Provided To Others? Yes  
Impact other research groups interested in/using our Anglerfish server 
URL http://anglerfish.cryst.bbk.ac.uk/
 
Description Running training workshops for students, postdocs and industrial scientists on CD spectroscopy 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Teaching Lectures and Practicals in multi-day workshops to provide new skills training and ideas and information for researchers both nationally and internationally
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018
 
Description annual talks for the public 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact UCL Science Centre Friday Evening Discourses and Birkbeck SET Talks for the Public talks on science for the public (5th, 6th form, and public) annually and lecture/tour at the Wellcome Collection talks

no actual impacts realised to date
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019,2020
 
Description international advisory boad (germany) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact international advisory board (Germany)
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015,2016,2017,2018
 
Description international advisory board (australia) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact international advisory board for scientific centre of excellence (australia)
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017