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Dr Alun Coker
University College London Division of Medicine, Royal Free C
Centre for Amyloidosis and Acute
London
NW32PF
Tel: 2074332764
Fax: 020 7433 2776
Appointment
  • Senior Lecturer
  • Inflammation
  • Div of Medicine
  • Faculty of Medical Sciences
 
 
Research Summary
The focus of my work is the use of single crystal X-ray diffraction to determine the three dimensional structure of various proteins and to use these structures to gain an understanding of the protein function at the atomic level. This information can then be used to direct mutagenesis experiments or in structure-based drug design.

Current projects:

Serum Amyloid P and Amyloidosis.
Serum amyloid P component (SAP) is a glycoprotein that binds a variety of ligands including proteins, glycosaminoglycans and DNA. SAP is universally associated with the amyloid deposits in all forms of amyloidoses including Alzheimer's disease. Small molecule ligands that displace SAP from amyloid fibres and thereby expose the fibres to proteolytic clearance mechanisms hold potential as therapeutic agents for the prevention and treatment of amyloidoses. We have developed an SAP targeting drug, CPHPC, which has already been in clinical testing for several years and shows promising efficacy in systemic amyloidosis. Its novel mechanism of action in depleting circulating SAP, discovered and elucidated through our collaboration with Prof. M. B. Pepys is patented worldwide. We have also identified a novel chaperone activity of SAP which may be of relevance to amyloidogenesis.
MhpC an alpha/beta hydrolase.
The alpha/beta hydrolases are a family of enzymes that sharing common structural features but without extensive sequence homology. Although the catalytic specificities vary quite widely rather similar arrangements of the catalytic site residues are observed. A conserved catalytic triad occupies similar position with respect to a common motif termed the nucleophile elbow. There is evidence for some members of the family that the conserved serine of this triad may function as a nucleophile as it does in the serine proteases. However, experimental evidence for MhpC suggests that an activated water molecule may form a gem-diol intermediate reminiscent of the aspartic proteases.  We have solved an X-ray structure of MhpC with a bound inhibitor in which the His and Ser of the catalytic triad straddle the inhibitor an arrangement not seen in the serine proteases, where the His-Ser dyad is directed towards the substrate. A similar arrangement is seen in the structures of two other alpha/beta hydrolases; an acetylcholinesterase complexed with Aricept, a drug used in the treatment of Alzhimer's, and a lipase complexed with its substrate. We are now trying to produce crystals of inactive MhpC mutants in complex with its substrate to define the structure of an enzyme substrate intermediate that would confirm our proposed mechanism.
Dengue Fever
Dengue is a mosquito-borne Flavivirus that is of immense global health importance.
Approximately 100 million people are infected with dengue virus each year and this number is set to rise with climate change and human migration. Clinical features of dengue range from mild infection to a life threatening disease called dengue haemorrhagic fever (DHF). Denge virus has a single-stranded, RNA genome that encodes a polyprotein that is cleaved into several structural and non-structural proteins. We are currently interested in nonstructural protein 1 (NS1) and nonstructural protein 5 (NS5). NS1 is thought to play critical roles in RNA replication and virion assembly but its exact function remains unclear. NS5 is a RNA-directed RNA polymerase and 5'-mythyltrasferase, but also seems to play a crucial role in inhibition of innate immunity. A critical advance in understanding the structure and function of theseprotein will inform new avenues of research into development of dengue vaccines and antivirals.
Academic Background
1998 PhD Doctor of Philosophy Birkbeck College
1990 MSc Master of Science Birkbeck College
1986 BSc Bachelor of Science University of Portsmouth
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