Professor of Protein Crystallography
Home page: http://www-structmed.cimr.cam.ac.uk
Research themes:Structural biology of medically-relevant proteins, Development of new likelihood-based methods for macromolecular crystallography
Description of research
Research in my group is in the field of protein crystallography. Crystallography is the primary method for determining the three-dimensional structure of a protein, which provides an essential framework for a detailed understanding of its biochemistry. We work both on extending the scope and power of the methods used in protein crystallography, and on applying those methods to determine new protein structures. In choosing what to study we focus on proteins involved in pathogenesis and disease, the structures of which can be exploited in the development of new therapies.
One focus of recent structural work has been on members of the serpin family, most of which undergo an extraordinary conformational change on cleavage by proteases. The structures of two hormone-binding globulins show how they harness this conformational change to deliver thyroxine and cortisol to their sites of action. Our work on angiotensinogen, the source of the hormone angiotensin, has shed new light on how blood pressure is modulated. We also have an interest in enzymes mutated in inherited metabolic diseases. The structures of galactocerebrosidase and iduronate sulphatase are helping to understand how mutations in these enzymes lead to Krabbe disease and Hunter syndrome.
In crystallographic theory, we focus on the understanding of probability distributions relating the structure factors that arise from the diffraction experiment. A detailed understanding of these probability distributions underlies new developments in maximum likelihood methods, which we are implementing in our program Phaser. The current version of Phaser can solve structures by molecular replacement (i.e. using the known structures of related proteins), by using the information from single-wavelength anomalous diffraction (SAD), and by a combination of the two. In a collaboration with the developers of the modelling program Rosetta, we have been excited to find that the combination of molecular replacement and advanced modelling can solve structures that elude previous methods.
Keywords: Non-inhibitory serpins, Maximum likelihood
Clinical conditions: Hypertension and pre-eclampsia, Lysosomal storage diseases, Krabbe disease, Hunter Syndrome
Methodologies: Macromolecular crystallography, Software development
Robin W Carrell, Janet E Deane, Willem H Ouwehand, Penelope E Stein, David Ron
Paul Adams, Tom Terwilliger, David and Jane Richardson, David Baker
Jackson RN, McCoy AJ, Terwilliger TC, Read RJ, Wiedenheft B (2015). X-ray structure determination using low-resolution electron microscopy maps for molecular replacement. Nat Protoc. 2015 Sep;10(9):1275-84.
Hill CH, Read RJ, Deane JE (2015). Structure of human saposin A at lysosomal pH. Acta Crystallogr F Struct Biol Commun. 2015 Jul;71(Pt 7):895-900.
Hill CH, Viuff AH, Spratley SJ, Salamone S, Christensen SH, Read RJ, Moriarty NW, Jensen HH, Deane JE (2015). Azasugar inhibitors as pharmacological chaperones for Krabbe disease. Chem Sci. 2015 May 20;6(5):3075-3086.
Sliwiak J, Dauter Z, Kowiel M, McCoy AJ, Read RJ, Jaskolski M (2015). ANS complex of St John’s wort PR-10 protein with 28 copies in the asymmetric unit: a fiendish combination of pseudosymmetry with tetartohedral twinning. Acta Crystallogr D Biol Crystallogr. 2015 Apr;71(Pt 4):829-43.
Chen R, Rato C, Yan Y, Crespillo-Casado A, Clarke HJ, Harding HP, Marciniak SJ, Read RJ, Ron D. G-actin provides substrate-specificity to eukaryotic initiation factor 2α holophosphatases. Elife. 2015 Mar 16;4.
Bunkóczi G, Wallner B, Read RJ (2015). Local error estimates dramatically improve the utility of homology models for solving crystal structures by molecular replacement. Structure. 2015 Feb 3;23(2):397-406.
Bunkóczi G, McCoy AJ, Echols N, Grosse-Kunstleve RW, Adams PD, Holton JM, Read RJ, Terwilliger TC (2015). Macromolecular X-ray structure determination using weak, single-wavelength anomalous data. Nat Methods. 2015 Feb;12(2):127-30.
Chan WL, Zhou A, Read RJ (2014). Towards engineering hormone-binding globulins as drug delivery agents. PLoS One. 2014 Nov 26;9(11):e113402.
Chen L, Kostadima M, Martens JH, Canu G, Garcia SP, Turro E, Downes K, Macaulay IC, Bielczyk-Maczynska E, Coe S, Farrow S, Poudel P, Burden F, Jansen SB, Astle WJ, Attwood A, Bariana T, de Bono B, Breschi A, Chambers JC; BRIDGE Consortium, Choudry FA, Clarke L, Coupland P, van der Ent M, Erber WN, Jansen JH, Favier R, Fenech ME, Foad N, Freson K, van Geet C, Gomez K, Guigo R, Hampshire D, Kelly AM, Kerstens HH, Kooner JS, Laffan M, Lentaigne C, Labalette C, Martin T, Meacham S, Mumford A, Nürnberg S, Palumbo E, van der Reijden BA, Richardson D, Sammut SJ, Slodkowicz G, Tamuri AU, Vasquez L, Voss K, Watt S, Westbury S, Flicek P, Loos R, Goldman N, Bertone P, Read RJ, Richardson S, Cvejic A, Soranzo N, Ouwehand WH, Stunnenberg HG, Frontini M, Rendon A (2014). Transcriptional diversity during lineage commitment of human blood progenitors. Science. 2014 Sep 26;345(6204):1251033.
Jackson RN, Golden SM, van Erp PB, Carter J, Westra ER, Brouns SJ, van der Oost J, Terwilliger TC, Read RJ, Wiedenheft B (2014). Structural biology. Crystal structure of the CRISPR RNA-guided surveillance complex from Escherichia coli. Science. 2014 Sep 19;345(6203):1473-9.
Echols N, Morshed N, Afonine PV, McCoy AJ, Miller MD, Read RJ, Richardson JS, Terwilliger TC, Adams PD(2014). Automated identification of elemental ions in macromolecular crystal structures. Acta Crystallogr D Biol Crystallogr. 2014 Apr;70(Pt 4):1104-14.
Sliwiak J, Jaskolski M, Dauter Z, McCoy AJ, Read RJ (2014). Likelihood-based molecular-replacement solution for a highly pathological crystal with tetartohedral twinning and sevenfold translational noncrystallographic symmetry. Acta Crystallogr D Biol Crystallogr. 2014 Feb;70(Pt 2):471-80.
Qi X, Chan WL, Read RJ, Zhou A, Carrell RW (2014). Temperature-responsive release of thyroxine and its environmental adaptation in Australians. Proc Biol Sci. 2014 Jan 29;281(1779):20132747.
Echols N, Moriarty NW, Klei HE, Afonine PV, Bunkóczi G, Headd JJ, McCoy AJ, Oeffner RD, Read RJ, Terwilliger TC, Adams PD (2014). Automating crystallographic structure solution and refinement of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr. 2014 Jan;70(Pt 1):144-54.
Hill CH, Graham SC, Read RJ, Deane JE (2013). Structural snapshots illustrate the catalytic cycle of β-galactocerebrosidase, the defective enzyme in Krabbe disease. Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20479-84.
Bunkóczi G, Echols N, McCoy AJ, Oeffner RD, Adams PD, Read RJ (2013). Phaser.MRage: automated molecular replacement. Acta Crystallogr D Biol Crystallogr. 2013 Nov;69(Pt 11):2276-86.
Terwilliger TC, Read RJ, Adams PD, Brunger AT, Afonine PV, Hung LW (2013). Model morphing and sequence assignment after molecular replacement. Acta Crystallogr D Biol Crystallogr. 2013 Nov;69(Pt 11):2244-50.
Oeffner RD, Bunkóczi G, McCoy AJ, Read RJ (2013). Improved estimates of coordinate error for molecular replacement. Acta Crystallogr D Biol Crystallogr. 2013 Nov;69(Pt 11):2209-15.
Uervirojnangkoorn M, Hilgenfeld R, Terwilliger TC, Read RJ (2013). Improving experimental phases for strong reflections prior to density modification. Acta Crystallogr D Biol Crystallogr. 2013 Oct;69(Pt 10):2039-49.
Chan WL, Carrell RW, Zhou A, Read RJ (2013). How changes in affinity of corticosteroid-binding globulin modulate free cortisol concentration. J. Clin. Endocrinol. Metab. 98: 3315–3322.
DiMaio F, Terwilliger TC, Read RJ, Wlodawer A, Oberdorfer G, Wagner U, Valkov E, Alon A, Fass D, Axelrod HL, Das D, Vorobiev SM, Iwaï H, Pokkuluri PR, Baker D (2011). Improving molecular replacement by density- and energy-guided protein structure optimization. Nature 473: 540-543.
Zhou A, Carrell RW, Murphy MP, Wei Z, Yan Y, Stanley PLD, Stein PE, Broughton Pipkin F, Read RJ (2010). A redox switch in angiotensinogen modulates angiotensin release. Nature 468: 108-111.
McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ (2007). Phaser crystallographic software. J. Appl. Cryst. 40: 658-674.
Professor Read is pleased to consider applications from prospective PhD students.