Professor of Protein Crystallography
Email: rjr27@cam.ac.uk
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.
Research focus
Keywords: Non-inhibitory serpins, Maximum likelihood
Clinical conditions: Hypertension and pre-eclampsia, Lysosomal storage diseases, Krabbe disease, Hunter Syndrome
Methodologies: Macromolecular crystallography, Software development
Cambridge collaborators
Robin W Carrell, Janet E Deane, Willem H Ouwehand, Penelope E Stein, David Ron
Other collaborators
Paul Adams, Tom Terwilliger, David and Jane Richardson, David Baker
Links
Key Publications
Agirre J, Atanasova M, Bagdonas H, Ballard CB, Baslé A, Beilsten-Edmands J, Borges RJ, Brown DG, Burgos-Mármol JJ, Berrisford JM, Bond PS, Caballero I, Catapano L, Chojnowski G, Cook AG, Cowtan KD, Croll TI, Debreczeni JÉ, Devenish NE, Dodson EJ, Drevon TR, Emsley P, Evans G, Evans PR, Fando M, Foadi J, Fuentes-Montero L, Garman EF, Gerstel M, Gildea RJ, Hatti K, Hekkelman ML, Heuser P, Hoh SW, Hough MA, Jenkins HT, Jiménez E, Joosten RP, Keegan RM, Keep N, Krissinel EB, Kolenko P, Kovalevskiy O, Lamzin VS, Lawson DM, Lebedev AA, Leslie AGW, Lohkamp B, Long F, Malý M, McCoy AJ, McNicholas SJ, Medina A, Millán C, Murray JW, Murshudov GN, Nicholls RA, Noble MEM, Oeffner R, Pannu NS, Parkhurst JM, Pearce N, Pereira J, Perrakis A, Powell HR, Read RJ, Rigden DJ, Rochira W, Sammito M, Sánchez Rodríguez F, Sheldrick GM, Shelley KL, Simkovic F, Simpkin AJ, Skubak P, Sobolev E, Steiner RA, Stevenson K, Tews I, Thomas JMH, Thorn A, Valls JT, Uski V, Usón I, Vagin A, Velankar S, Vollmar M, Walden H, Waterman D, Wilson KS, Winn MD, Winter G, Wojdyr M, Yamashita K. The CCP4 suite: integrative software for macromolecular crystallography. Acta Crystallogr D Struct Biol. 2023 Jun 1;79(Pt 6):449-461
Read RJ, Millán C, McCoy AJ, Terwilliger TC. Likelihood-based signal and noise analysis for docking of models into cryo-EM maps. Acta Crystallogr D Struct Biol. 2023 Apr 1;79(Pt 4):271-280.
Millán C, McCoy AJ, Terwilliger TC, Read RJ. Likelihood-based docking of models into cryo-EM maps. Acta Crystallogr D Struct Biol. 2023 Apr 1;79(Pt 4):281-289.
Jianwei L, Jobichen C, Machida S, Meng S, Read RJ, Hongying C, Jian S, Yuan YA, Sivaraman J. Structures of apo Cas12a and its complex with crRNA and DNA reveal the dynamics of ternary complex formation and target DNA cleavage. PLoS Biol. 2023 Mar 14;21(3):e3002023.
Acta Crystallogr D Struct Biol. 2023 Mar 1;79(Pt 3):234-244.
Oeffner RD, Croll TI, Millán C, Poon BK, Schlicksup CJ, Read RJ, Terwilliger TC. Putting AlphaFold models to work with phenix.process_predicted_model and ISOLDE. Acta Crystallogr D Struct Biol. 2022 Nov 1;78(Pt 11):1303-1314.
Terwilliger TC, Poon BK, Afonine PV, Schlicksup CJ, Croll TI, Millán C, Richardson JS, Read RJ, Adams PD. Improved AlphaFold modeling with implicit experimental information. Nat Methods. 2022 Nov;19(11):1376-1382.
Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10. Nat Commun. 2022 May 3;13(1):2395.
CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythaemia. Blood. 2022 Jan 20:blood.2021013113.
Implications of AlphaFold2 for crystallographic phasing by molecular replacement. Acta Crystallogr D Struct Biol. 2022 Jan 1;78(Pt 1):1-13.
Submission of structural biology data for review purposes. IUCrJ. 2021 Dec 16;9(Pt 1):1-2.
Baker EN, Bond CS, Garman EF, Newman J, Read RJ, van Raaij MJ. Submission of structural biology data for review purposes. Acta Crystallogr D Struct Biol. 2021 Dec 1;77(Pt 12):1477-1478.
Baker EN, Bond CS, Garman EF, Newman J, Read RJ, van Raaij MJ. Submission of structural biology data for review purposes. Acta Crystallogr F Struct Biol Commun. 2021 Dec 1;77(Pt 12):435-436.
Millán C, Keegan RM, Pereira J, Sammito MD, Simpkin AJ, McCoy AJ, Lupas AN, Hartmann MD, Rigden DJ, Read RJ. Assessing the utility of CASP14 models for molecular replacement. Proteins. 2021 Dec;89(12):1752-1769.
Baek M, DiMaio F, Anishchenko I, Dauparas J, Ovchinnikov S, Lee GR, Wang J, Cong Q, Kinch LN, Schaeffer RD, Millán C, Park H, Adams C, Glassman CR, DeGiovanni A, Pereira JH, Rodrigues AV, van Dijk AA, Ebrecht AC, Opperman DJ, Sagmeister T, Buhlheller C, Pavkov-Keller T, Rathinaswamy MK, Dalwadi U, Yip CK, Burke JE, Garcia KC, Grishin NV, Adams PD, Read RJ, Baker D. Accurate prediction of protein structures and interactions using a three-track neural network. Science. 2021 Aug 20;373(6557):871-876.
Hatti KS, McCoy AJ, Read RJ. Likelihood-based estimation of substructure content from single-wavelength anomalous diffraction (SAD) intensity data. Acta Crystallogr D Struct Biol. 2021 Jul 1;77(Pt 7):880-893.
Adaptive Cartesian and torsional restraints for interactive model rebuilding. Acta Crystallogr D Struct Biol. 2021 Apr 1;77(Pt 4):438-446.
Angiotensinogen and the Modulation of Blood Pressure. Front Cardiovasc Med. 2021 Mar 18;8:645123.
Caballero I, Sammito MD, Afonine PV, Usón I, Read RJ, McCoy AJ. Detection of translational noncrystallographic symmetry in Patterson functions. Acta Crystallogr D Struct Biol. 2021 Feb 1;77(Pt 2):131-141.
Usón I, Ballard CC, Keegan RM, Read RJ. Integrated, rational molecular replacement. Acta Crystallogr D Struct Biol. 2021 Feb 1;77(Pt 2):129-130.
McCoy AJ, Stockwell DH, Sammito MD, Oeffner RD, Hatti KS, Croll TI, Read RJ. Phasertng: directed acyclic graphs for crystallographic phasing. Acta Crystallogr D Struct Biol. 2021 Jan 1;77(Pt 1):1-10.
Terwilliger TC, Sobolev OV, Afonine PV, Adams PD, Read RJ. Density modification of cryo-EM maps. Acta Crystallogr D Struct Biol. 2020 Oct 1;76(Pt 10):912-925.
Terwilliger TC, Ludtke SJ, Read RJ, Adams PD, Afonine PV. Improvement of cryo-EM maps by density modification. Nat Methods. 2020 Sep;17(9):923-927.
Read RJ, Oeffner RD, McCoy AJ. Measuring and using information gained by observing diffraction data. Acta Crystallogr D Struct Biol. 2020 Mar 1;76(Pt 3):238-247.
Hatti KS, McCoy AJ, Oeffner RD, Sammito MD, Read RJ. Factors influencing estimates of coordinate error for molecular replacement. Acta Crystallogr D Struct Biol. 2020 Jan 1;76(Pt 1):19-27.
Liebschner D, Afonine PV, Baker ML, Bunkóczi G, Chen VB, Croll TI, Hintze B, Hung LW, Jain S, McCoy AJ, Moriarty NW, Oeffner RD, Poon BK, Prisant MG, Read RJ, Richardson JS, Richardson DC, Sammito MD, Sobolev OV, Stockwell DH, Terwilliger TC, Urzhumtsev AG, Videau LL, Williams CJ, Adams PD. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr D Struct Biol. 2019 Oct 1;75(Pt 10):861-877.
Lentaigne C, Greene D, Sivapalaratnam S, Favier R, Seyres D, Thys C, Grassi L, Mangles S, Sibson K, Stubbs M, Burden F, Bordet JC, Armari-Alla C, Erber W, Farrow S, Gleadall N, Gomez K, Megy K, Papadia S, Penkett CJ, Sims MC, Stefanucci L, Stephens JC, Read RJ, Stirrups KE, Ouwehand WH, Laffan MA; NIHR BioResource, Frontini M, Freson K, Turro E. Germline mutations in the transcription factor IKZF5 cause thrombocytopenia. Blood. 2019 Dec 5;134(23):2070-2081.
Helliwell JR, Minor W, Weiss MS, Garman EF, Read RJ, Newman J, van Raaij MJ, Hajdu J, Baker EN. Findable Accessible Interoperable Re-usable (FAIR) diffraction data are coming to protein crystallography. Acta Crystallogr D Struct Biol. 2019 May 1;75(Pt 5):455-457
Jamshidiha M, Pérez-Dorado I, Murray JW, Tate EW, Cota E, Read RJ. Coping with strong translational noncrystallographic symmetry and extreme anisotropy in molecular replacement with Phaser: human Rab27a. Acta Crystallogr D Struct Biol. 2019 Mar 1;75(Pt 3):342-353.
Yan Y, Zhou A, Carrell RW, Read RJ. Structural basis for the specificity of renin-mediated angiotensinogen cleavage. J Biol Chem. 2019 Feb 15;294(7):2353-2364.
Dahabiyeh LA, Tooth D, Carrell RW, Read RJ, Yan Y, Pipkin FB, Barrett DA. Measurement of the total angiotensinogen and its reduced and oxidised forms in human plasma using targeted LC-MS/MS. Anal Bioanal Chem. 2019 Jan;411(2):427-437.
Afonine PV, Poon BK, Read RJ, Sobolev OV, Terwilliger TC, Urzhumtsev A, Adams PD. Real-space refinement in PHENIX for cryo-EM and crystallography. Acta Crystallogr D Struct Biol. 2018 Jun 1;74(Pt 6):531-544.
Millán C, Sammito MD, McCoy AJ, Nascimento AFZ, Petrillo G, Oeffner RD, Domínguez-Gil T, Hermoso JA, Read RJ, Usón I. Exploiting distant homologues for phasing through the generation of compact fragments, local fold refinement and partial solution combination. Acta Crystallogr D Struct Biol. 2018 Apr 1;74(Pt 4):290-304.
McCoy AJ, Oeffner RD, Millán C, Sammito M, Usón I, Read RJ. Gyre and gimble: a maximum-likelihood replacement for Patterson correlation refinement. Acta Crystallogr D Struct Biol. 2018 Apr 1;74(Pt 4):279-289.
Oeffner RD, Afonine PV, Millán C, Sammito M, Usón I, Read RJ, McCoy AJ. On the application of the expected log-likelihood gain to decision making in molecular replacement. Acta Crystallogr D Struct Biol. 2018 Apr 1;74(Pt 4):245-255.
Read RJ, McCoy AJ. Maximum-likelihood determination of anomalous substructures. Acta Crystallogr D Struct Biol. 2018 Feb 1;74(Pt 2):98-105.
Demydchuk M, Hill CH, Zhou A, Bunkóczi G, Stein PE, Marchesan D, Deane JE, Read RJ. Insights into Hunter syndrome from the structure of iduronate-2-sulfatase. Nat Commun. 2017 Jun 8;8:15786.
Chiu W, Holton J, Langan P, Sauter NK, Schlichting I, Terwilliger T, Martin JL, Read RJ, Wakatsuki S. Responses to `Atomic resolution’: a badly abused term in structural biology. Acta Crystallogr D Struct Biol. 2017 Apr 1;73(Pt 4):381-383.
McCoy AJ, Oeffner RD, Wrobel AG, Ojala JR, Tryggvason K, Lohkamp B, Read RJ. Ab initio solution of macromolecular crystal structures without direct methods. Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3637-3641.
Dore AS, Bortolato A, Hollenstein K, Cheng RKY, Read RJ, Marshall FH. Decoding Corticotropin-Releasing Factor Receptor Type 1 Crystal Structures. Curr Mol Pharmacol. 2017;10(4):334-344.
Carrell RW, Read RJ. How serpins transport hormones and regulate their release. Semin Cell Dev Biol. 2016 Dec 24. pii: S1084-9521(16)30478-5.
Felix J, Kandiah E, De Munck S, Bloch Y, van Zundert GC, Pauwels K, Dansercoer A, Novanska K, Read RJ, Bonvin AM, Vergauwen B, Verstraete K, Gutsche I, Savvides SN. Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF. Nat Commun. 2016 Nov 7;7:13228.
Weiss MS, Diederichs K, Read RJ, Panjikar S, Van Duyne GD, Matera AG, Fischer U, Grimm C. A critical examination of the recently reported crystal structures of the human SMN protein. Hum Mol Genet. 2016 Aug 29. pii: ddw298.
Nolan K, Kattamuri C, Rankin SA, Read RJ, Zorn AM, Thompson TB. Structure of Gremlin-2 in Complex with GDF5 Gives Insight into DAN-Family-Mediated BMP Antagonism. Cell Rep. 2016 Aug 23;16(8):2077-86.
Huang X, Zheng Y, Zhang F, Wei Z, Wang Y, Carrell RW, Read RJ, Chen GQ, Zhou A (2016). Molecular Mechanism of Z α1-antitrypsin Deficiency. J Biol Chem. 2016 Jul 22;291(30):15674-86.
Read RJ, McCoy AJ (2016). A log-likelihood-gain intensity target for crystallographic phasing that accounts for experimental error. Acta Crystallogr D Struct Biol. 2016 Mar 1;72(Pt 3):375-87.
Martin JL, Read RJ, Wakatsuki S (2016). Expanding beyond biological crystallography. Acta Crystallogr D Struct Biol. 2016 Jan;72(Pt 1):1.
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.
PhD Supervisions
Professor Read is pleased to consider applications from prospective PhD students.
Haematology at Cambridge