Geerten W. Vuister

Structural biology of Ca2+-transport regulation complexes

Gertee

Research Summary

The research in my group is focused in two main areas: Firstly, on protein domains involved in the regulation of ion transport and the regulation and assembly of active biological complexes. Secondly, on the development of methods to improve NMR-derived structures, develop automated tools for structure quality assessment and data evaluations, and design new NMR sequences for the study of dynamics and interactions.

A particular area of interest is understanding the regulatory mechanisms that govern Ca2+ fluxes across membranes, which are crucial in many cellular processes. The systems we are currently studying involves the Na+/Ca2+ exchanger (NCX), a highly ubiquitous ion transporter that constitutes the dominant Ca2+ efflux mechanism in heart and sensory neurons, and the family of Transient Receptor Potential (TRP) channels, in particular the vaniloid TRPV5/6 subtypes. We use high-resolution Nuclear Magnetic Resonance spectroscopy, together with other structural methods like SAXS and homology modelling, to understand the atomic detail underpinning the regulation of these channels. We then combine this information with data from biophysical and ultimately cell based assays to gain a comprehensive knowledge regarding the structure and function of these channels. These insights will hopefully aid the successful development of new drugs targeting the numerous devastating diseases associated with aberrant Ca2+ signalling, such as multiple sclerosis, heart disease, stroke, osteoporosis and Alzheimer’s disease.

For many years, my research group has been involved in the development of computational tools for both the analysis and validation of structural NMR data. The aim of these tools is to ensure that NMR structures adequately reflect the experimental data and are reliable in terms of overall and local quality. Currently, our efforts are focused within the Collaborative Computational Project for NMR (CCPN, MRC-funded). The aim of CCPN is to develop a graphics-based, adaptable and easily extendable software platform for users which covers all aspects of NMR data analysis from spectrum visualisation to structure calculation and validation. Through its active outreach programme, CCPN also promotes the exchange of knowledge, provides training, and supports best practices in the NMR community.

Overall architecture of the sodium-calcium exchanger (NCX). Shown are the trans membrane homology model, two Ca2+ sensing domains (CBD1, red, and CBD2, green), a Catenin-like domain (CLD, blue) and two loop regions that connect to the trans-membrane (TM) region. Schematic domain structure is displayed on top.
Overall architecture of the sodium-calcium exchanger (NCX). Shown are the trans membrane homology model,
two Ca2+ sensing domains (CBD1, red, and CBD2, green), a Catenin-like domain (CLD, blue) and two loop
regions that connect to the trans-membrane (TM) region. Schematic domain structure is displayed on top.

The CcpNmr version-3 Analysis package comprises four programs; AnalysisAssign is shown. Tools for structural refinement and conformational analysis of NMR ensembles are implemented in AnalysisStructure. The figure shows the effects of structure refinement of the the NMR ensembles of apo (PDB:2L28) and holo (i.e. both NADHP and Trimethoprim bound; PDB:1LUD) forms of of Dihydrofolate reductase, diplayed on a scoring PCA space.
The CcpNmr version-3 Analysis package comprises four programs; AnalysisAssign is shown. Tools for structural
refinement and conformational analysis of NMR ensembles are implemented in AnalysisStructure. The figure shows
the effects of structure refinement of the the NMR ensembles of apo (PDB:2L28) and holo (i.e. both NADHP
and Trimethoprim bound; PDB:1LUD) forms of of Dihydrofolate reductase, diplayed on a scoring PCA space.

Key Publications

Group Members:

Ed Brooksbank, Luca Mureddu

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