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The Edinburgh Biomolecular NMR Unit Members


   Professor of Structural Biology        Lecturer in NMR             Lecturer in Structural Biology 
Prof. Paul N. Barlow Dr. Dusan Uhrin Dr. Janice Bramham
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   Manager of the NMR Facilities     Postdoctoral Researchers
Dr. Juraj Bella
Dr. Andrew Herbert
Dr. Graeme Ball
Dr. David Kavanagh, MD
Dr. Marie Phelan
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Postgraduate Students Research Assistants 
Bärbel Blaum
Chris Fenton
Henry Hocking
Lan Jin
Marc Lenoir
Isabell Pechtl
Elin Pless
Patience Tetteh-Quarcoo
Christoph Schmidt
Dinesh Soares
 
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Previous Group Members
Dr. Emma Beatty
Dr. Gordon Black
Dr. Stanislas Blein
Dr. K. Bromek
Dr. Eve Brook
Claire  Egan
Dr. C. Henderson
Dr. Huw Jenkins
Dr. Lena Kask
Dr. Marina Kirkitadze
Dr. Jo O'Leary
Dr. Kirsten Lillie
Ursula Lodge
Dr. Rosie Mallin
Dr. Nicholas Mullin
Dr. John Parkinson
Dr. Tran N. Pham
Dr. Julia Richardson
Dr. Philip Robinson
Dr. Brian O. Smith
Dr. Alison Soteriou
Dr. Helen McSparron
Dr. Que Van
Dr. Robert Wakefield
Dr. Michael Wenzler
Dr. Alan Wiles
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Former Visiting Scientists
Prof. Edward Hawrot
(Brown University)
Dr. Jonathan Hannan
(University of  Colorado) Dr. Mark Smith
(Massey University)
Dr. Pat Edwards
(Massey University)
Dr. Tibor Liptaj
(Slovak Technical
University)


Group Members Research Interests

Prof. Paul N. Barlow


email: paul.barlow@ed.ac.uk home page

Professor of Structural Biology

Our research focus is on protein structure. The main tool we use is solution state NMR, but we also employ calorimetry, circular dichroism, hydrodynamics, molecular modelling, mass spectrometry and fluorescence spectroscopy to complement the high-resolution structure information.

For example, we are interested in multi-modular proteins such as are found in the complement system. Many of these are large, extended, flexible and glycosylated. We use NMR to study small fragments of two or three modules, calorimetry to study module-module interactions and a combination of hydrodynamics and molecular modelling to extrapolate to bigger fragments or complete proteins.

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Dr. Dusan Uhrin

email: dusan.uhrin@ed.ac.uk home page

Lecturer in NMR spectroscopy

My research deals with the application of NMR to interesting biological problems as well as with the development of new techniques for biomolecular NMR spectroscopy.

At the heart of my research are the studies of protein-glycosaminoglycan interactions. We are investigating several polyanion binding sites of factor H, a crucial regulator of the alternative pathway of complement. In another study we are characterising interaction of heparan and dermatan sulfates with NK1, an isoform of the hepatocyte growth factor/scatter factor. Understanding these interactions on a molecular level can lead to rational design of drugs and vaccines.

I am developing new NMR techniques for the conformational analysis of carbohydrates, focusing in particular on the methods for the measurement of residual dipolar coupling constants and long-range carbon-carbon coupling constants. We are also developing new NMR techniques for the solution structure determination of protein-GAG complexes.
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Dr. Janice Bramham

email: jbramham@staffmail.ed.ac.uk home page

Lecturer in Structural Biology

I am interested in the three-dimensional structures and intrinsic dynamics of biological macromolecules with the ultimate aim of understanding their structure-function relationships. My current work is focused upon proteins of the human complement system, which plays an essential role in our immune response to infection.

I am determining tertiary structures and investigating specific protein:protein interactions that occur in macromolecular assemblies. The principal technique I employ is high-resolution, multi-dimensional NMR spectroscopy which I complement with other biophysical techniques, such as mass spectrometry and isothermal titration calorimetry.

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Dr. Juraj Bella

email: juraj.bella@ed.ac.uk

NMR Facilities Manager
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Dr. Andrew Herbert

email: a.herbert@ed.ac.uk


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Dr. Graeme Ball

email: graeme.ball@ed.ac.uk


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Dr. David Kavanagh

email: davidkavanagh@doctors.org.uk


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Dr. Marie Phelan

email: marie.phelan@ed.ac.uk

The membrane attack complex (MAC) is a key component at the terminus of the comple- ment pathways; it has the ability to kill cells by puncturing the plasma membrane resulting in cytolysis. Initiated by the proteolytic cleavage of C5, the subsequent formation of the MAC is a non-catalytic, self-assembly process whereby five soluble proteins rapidly organise themselves into a membrane-penetrating macromolecular complex. My research, utilising high-field NMR spectroscopy, aims to provide an insight into the tertiary structures of the MAC proteins. I am investigating the protein-protein interactions and conformational changes involved in the MAC assembly process and in the maintenance of the stable macromolecular complex. This work, developed and coordinated by Dr Janice Bramham, is funded by the MRC.
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Bärbel Blaum

email: baerbel.blaum@ed.ac.uk

Glycosaminoglycan-Protein interaction are thought to be at the centre of important processes of host recognition within the human Complement System. My PhD work focuses on the purification and characterization of small heparin-derived oligosaccharides and subsequent binding studies to Complement Factor H modules. I aim to characterize the GAG-protein interaction on a molecular level using mostly NMR based techniques. In particular, Paramagnetic Relaxation Enhancements generated by spin-labeled oligosaccharides prepared by our collaborators.
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Chris Fenton

email: chris.fenton@ed.ac.uk

I am working on a solution structure of a factor H module belonging to one of its three heparin binding sites. Factor H is an immune system regulator of the complement system. It works by preventing the alternative pathway of the complement system becoming active on host cell membranes, which would otherwise lead to cell lysis. To recognise host from non-host cell membranes, factor H binds to polyanions found on the surface of host cells.

Our collaborators have confirmed, by Gel Mobility Shift Assay, that our recombinant module does bind to a fully sulfated heparin-derived tetrasaccharide. This finding broadens the scope of my PhD program to include the characterisation of the interaction between fH and heparin sulphate/heparin tetrasaccharides using NMR.
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Henry Hocking

email: H.G.Hocking@sms.ed.ac.uk

My PhD project focuses on the regulatory region of the human complement regulator factor H. This region, located at the N-terminus of factor H, is made up of four CCP modules and is responsible for accelerating the decay of the C3 and C5 convertases of the alternative pathway as well as acting as a cofactor to the proteolytic degradation of C3b by factor I. These two modes of action provide protection of host cells from non-specific attack by the alternative pathway of complement.

My main objective is to solve the solution structure of overlapping module pairs (~14 kDa per pair) within this regulatory region in order to reconstruct the entire functional site. My current work involves cloning, expression, purification of the different module pairs followed by their structure determination using NMR spectroscopy methods. Triple module constructs are also being studied to validate this approach and to further assess the inter-modular orientations and dynamics within this region.
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Lan Jin

email: L.Jin@sms.ed.ac.uk

I study the gas phase structures of heparin-derived oligosaccharides by using ion mobility mass spectrometry and molecular modelling. In solution I use various techniques of NMR spectroscopy to study a conformation of a fully sulfated heparin-derived tetrasaccharide.

In our efforts to characterize the conformation of glycosidic linkages of carbohydrates I am working on the development of techniques for the measurement of long-range carbon-carbon coupling constants in natural abundance 13C samples. Further work is in progress on the development of robust methods for the measurement of proton-proton residual dipolar coupling constants of carbohydrates.
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Marc Lenoir

email: m.lenoir@sms.ed.ac.uk

Tumors growth is often associated with neovascularisation events which can be detected via specific markers during the earliest stages of the cancer progression. It has been shown that the integrin family potentially represents one of these markers. General Electric Health has designed a series of cyclic peptides which are aimed at binding specifically integrin avbIII and by carrying a radio labelling metal are detectable by imaging techniques. Our goal is to study the three dimensional structure of these peptides by using NMR spectroscopy.
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Isabell Pechtl

email: I.C.Pechtl@sms.ed.ac.uk

For my PhD project I am employing a combination of fluorescence resonance energy transfer (FRET) and NMR to study the link between conformation and function in factor H. Factor H is composed of 20 CCP modules (~1200 amino acids). Factor H regulates the amplification of the alternative complement pathway and sequence variations in factor H (both mutations and SNPs) are linked to several diseases of the kidneys and eye.

My goal is to use FRET (fluorescence resonance energy transfer) to measure long-range interatomic distances in factor H and thereby support NMR-based structural investigations that rely on short-range (NOE) restraints. I shall also use paramagnetic NMR to obtain further structural restraints.

By using site-directed mutagenesis, cysteine residues can be introduced into the CCP modules of factor H at strategic points and subsequently be used for attachment of fluorescent tags such as caged lanthanides that have the added advantage of being paramagnetic.
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Elin Pless

email: elin.pless@ed.ac.uk

My PhD project involves the GABAB receptor, which is a membrane protein involved in synaptic transmission in various brain regions and forms the basis of a powerful and versatile inhibitory system in the mammalian brain.

The N-terminal region of the GABABR1a consists of two complement protein modules (CCP-modules), which are highly conserved protein sequences. The CCP-modules seem to function as binding sites for macromolecules. The main aim of my project is to investigate possible interactions between the GABABR1a CCP modules and various proteins. This is explored by using the Yeast Two Hybrid system (YTH), Biacore and different protein pull-down methods as well as functional studies in the model system Xenopus Laevis.
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Patience Tetteh-Quarcoo

email: elin.pless@ed.ac.uk

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Christoph Schmidt

email:s0460219@sms.ed.ac.uk

My PhD project deals with the module-module orientation and structure of the central CCP modules (12 to 14) from the fluid phase regulator of the alternative pathway - factor H. Distinct module orientation/interactions are likely to originate from the diverse CCP module sequences and the variable type and numbers of residues within the intervening linkers. This is impossible, at present, to model and therefore there is a particular interest in the experimental determination of module-module orientations.

The use of paramagnetic probe molecules in the field of NMR has become a powerful technique with which to refine solution structures. It is valuable for obtaining long-range restrains, up to a maximum distance of 40 Å. It is therefore particularly useful for refining the structure of extended loops, or obtaining intermodular orientations within multidomain proteins where few NOEs occur between modules. One aim of this project is to apply this technique to determine the relative orientation of the central CCP modules (12 to 14) of factor H.

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Dinesh Soares

email: D.C.Soares@sms.ed.ac.uk

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