Department of Biochemistry University of Oxford Department of Biochemistry
University of Oxford
South Parks Road
Oxford OX1 3QU

Tel: +44 (0)1865 613200
Fax: +44 (0)1865 613201
Image showing the global movement of lipids in a model planar membrane
Matthieu Chavent, Sansom lab
Anaphase bridges in fission yeast cells
Whitby lab
Lactose permease represented using bending cylinders in Bendix software
Caroline Dahl, Sansom lab
Epithelial cells in C. elegans showing a seam cell that failed to undergo cytokinesis
Serena Ding, Woollard lab
Collage of Drosophila third instar larva optic lobe
Lu Yang, Davis lab
First year Biochemistry students at a practical class
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Simon Newstead
Structural and Functional Studies of Membrane Proteins involved in nutrient uptake and drug transport

Co-workers: Dr Jo Parker, Dr Gurdeep Minhas, Dr Gabriel Kuteyi, Dr Richard Payne, Dr Jason Yau, Mr Ashley Gillum, Mr Philip Braeuer, Mr Oliver Adams, Mr Tomas Pascoa, Mr Zhiyi Wu

Alumni:  Dr Oleg Sitsel (EMBO Fellow), Dr Sabrina Schulze (EMBO Fellow), Dr Katharina Jungnickel (Marie Curie ITN Graduate Student), Dr Nicolae Solcan (Wellcome Trust Cellular Structural Biology Graduate Student), Dr Sonya Hanson (NIH-OxCam Graduate Student), Dr John H. Beale (MRC Graduate Student).

Website: http://www.newsteadgroup.org

Research in my laboratory focuses on understanding how nutrient transporters function at a molecular level. In humans many of the transport proteins involved in absorbing nutrients from our diet, such protein, sugar and fats, are also responsible for drug transport and distribution into specific organs, such as the central nervous system, liver and kidneys. Nutrient transporters therefore have a profound impact on the pharmacokinetic properties of many administered drugs with clear medical advantages to understanding their biochemistry.

Peptide transporters belong to one such family of integral membrane transporters, which in mammals are the major route of dietary peptide absorption in the small intestine and kidneys. In humans they belong to the Solute Carrier (SLC) 15 gene family and called PepT1 and PepT2. Both PepT1 and PepT2 are of significant pharmaceutical interest due to their ability to actively uptake a number of clinically important drugs, such as beta-lactam antibiotics, antivirals and HIV protease inhibitors. Recent developments in drug delivery technology have targeted PepT1 and PepT2 to improve the pharmacokinetic properties of such drugs, including their uptake and retention within the body. Following attachment of amino acids or small peptides to a drug that has poor absorption properties, these called peptide pro drugs are now recognized by PepT1 and transported into the body following oral administration (Figure A). The potential of utilizing PepT1 and PepT2 as universal drug delivery and retention systems represents a profound and transformative new development in engineered drug bioavailiabity.

One of the key goals of our research is to extend the use of protein crystallography, single particle cryo-EM and in vitro biochemical analysis to provide novel insights into the molecular details underpinning the observed peptide and drug recognition properties within the SLC15 peptide transporter family.

The group is also focused on several additional families of secondary active SLC transporters linked to drug transport. These include the SLC36 and 38 families of amino acid transporters and the SLC35 family of nucleotide sugar transporters.

Membrane protein crystal screen development: The MemGold family.

The development of new methods to determine the crystal structures of membrane proteins is also an important part of our research. In addition to work in developing expression and screening technologies to identify suitable targets for biophysical study, we are also data mining the Protein Data Bank (PDB) to uncover emerging trends in alpha helical membrane protein crystallization. This information is then used to develop more sophisticated membrane protein crystallization screens. We have recently launched complimentary screens to the highly successful MemGold screen, which was launched in 2007, called MemGold II and MemAdvantage. MemGold II employs information from a range of recently determined eukaryotic membrane protein structures, whilst MemAdvantage is the first additive screen designed specifically for membrane protein crystal optimization. These screens are available through our industrial partner Molecular Dimensions Ltd.

Selected Publications

  1. Parker, JL. & Newstead, S. Structural basis of nucleotide sugar transport across the Golgi membrane. 2017 Nature 551, 521-524.
  2. Parker, JL. et al. Proton movement and coupling in the POT family of peptide transporters. 2017 PNAS 114,13182-13187.
  3. Byrne, EXF. et al. Structutral basis of Smoothened regulation by its extracellular domains. 2016 Nature 535, 517-522.
  4. Stockbridge, R.B. et al. Crystal structures of a double-barrelled fluoride ion channel. 2015 Nature 525, 548-51.
  5. Parker, JL. & Newstead, S. Molecular basis of nitrate uptake by the plant nitrate transporter NRT1.1. 2014 Nature 507, 68-72.
More Publications...


Recent news articles relating to research in the Newstead group:

Nitrate transporter structure paves the way for exciting new areas of work
Wellcome Trust Investigator Award success for Simon Newstead
 

 

Research Images



Figure A: PepT1 and PepT2 play key roles in mediated drug transport in the human body. Illustrated here the concept of peptide pro-drug transport



Figure B: Alternating access mechanism of transport in the POT family, determined through structural and biochemical studies undertaken in the group

 

Figure C: Crystal structure of PepTSo, a bacterial homologue of PepT1, shown in an simulated POPC bilyer used to study protein dynamics via molecular dynamics. Valacicolvir, a commonly prescribed peptide pro-drug transported into the body via PepT1


Contact:simon.newstead@bioch.ox.ac.uk