Emil F Pai, DSc

Knowledge of the three-dimensional structure of a given protein is an absolutely essential prerequisite for fully understanding the chemical basis of a catalytic mechanism of an enzyme or for interpreting the way structural proteins like e.g. actin interact with each other. In my lab, we use X-ray crystallography in connection with computer graphics and refinement programs to establish the molecular architecture of proteins. We are eager to integrate our results with biochemical and molecular-biological data, either collected in our laboratory or available through collaboration with specialists in the field. There are always several proteins in the laboratory from which we try to grow crystals.

Recent proteins for which we have solved the three-dimensional structure include:
  • Orotidine 5'-phosphate decarboxylase from H. sapiens, P. falciparum and M. thermoautotrophicum
    ODCase is the most proficient enzyme known. It catalyzes the conversion of orotidine-5'-mono-phosphate (OMP) to uridine 5'-monophosphate (UMP), the last step in the de novo biosynthesis of pyrimidine nucleotides enhancing the decarboxylation rate by 17 orders of magnitude without the help of any cofactors or metal ions. The crystal structures of the apo-enzyme as well as about 50 ligand complexes have been determined, most of them at atomic resolution. We identified new catalytic properties of the enzyme and described surprising reactions. Several ligands are potential lead compounds for anti-malaria and anti-cancer drugs. In collaboration with medicinal chemists we are pursuing the optimization of those molecules.
  • Structural transitions of the prion protein
    In collaboration with several laboratories, we are exploring the still unknown mechanism that converts the normal prion protein (PrP-C) to its toxic, infectious, and aggregated misfolded state (PrP-Sc). With antibodies developed in the team's labs that specifically detect PrP-Sc and misfolded PrP--but do not bind with the normal prion protein--the researchers hope to elucidate both the 3-D structure of PrP-Sc immediately after the conversion process ensues. As a first step towards this goal, we have determined the 3-D structure of PrP from rabbit, an animal that is resistant to prion infection, and of several of its mutants. We have also solved the structures of PrP-Sc-specific antibodies.
  • CorA--a Mg++ transporter from T. maritime
    Recently, we determined the structure of a pentameric membrane protein that imports Mg++ -ions into the cell. In collaboration with several colleagues' laboratories, we continue to investigate its mechanism applying molecular biology, electrophysiology, AFM and crystallographic techniques. We have created nearly 100 mutants and have crystallized several of them. Computational approaches pursued in collaboration with colleagues at the Hospital for Sick Children have identified potential domain movements crucial for the transport mechanism.
  • Xanthine oxidoreductases from human, cow and rat milk
    Milk xanthine oxidoreductase is an enzyme that has served as a benchmark for complex flavoproteins and molybdo-enzymes for over 100 years. In mammals, it is synthesized in its dehydrogenase form (XDH) but can be converted to an oxidase form (XO), either reversibly by oxidizing sulfhydryl groups or irreversibly by limited proteolytic digestion. The enzyme is a target for drugs directed against gout and hyperuricemia. The conversion of XDH to XO is of interest as it has been implicated in diseases characterized by oxygen radical-induced damage (e.g., postischemic reperfusion injury). We have determined the structures of both forms of the enzyme, described the changes associated with the XDH to XO transition and located the binding sites of substrates and drug molecules.

Related Links

MAbs. 2018 Jul 03;:
Dhagat U, Hercus TR, Broughton SE, Nero TL, Cheung Tung Shing KS, Barry EF, Thomson CA, Bryson S, Pai EF, McClure BJ, Schrader JW, Lopez AF, Parker MW
Leukemia. 2018 Jun 08;:
Barghout SH, Patel PS, Wang X, Xu GW, Kavanagh S, Halgas O, Zarabi SF, Gronda M, Hurren R, Jeyaraju DV, MacLean N, Brennan S, Hyer ML, Berger A, Traore T, Milhollen M, Smith AC, Minden MD, Pai EF, Hakem R, Schimmer AD
Sci Rep. 2018 Jun 05;8(1):8654
Ghodrati F, Mehrabian M, Williams D, Halgas O, Bourkas MEC, Watts JC, Pai EF, Schmitt-Ulms G
ChemMedChem. 2018 Apr 06;:
De Gasparo R, Brodbeck-Persch E, Bryson S, Hentzen NB, Kaiser M, Pai EF, Krauth-Siegel RL, Diederich F
J Inherit Metab Dis. 2017 Feb 15;:
Wortmann SB, Chen MA, Colombo R, Pontoglio A, Alhaddad B, Botto LD, Yuzyuk T, Coughlin CR, Descartes M, Grűnewald S, Maranda B, Mills PB, Pitt J, Potente C, Rodenburg R, Kluijtmans LA, Sampath S, Pai EF, Wevers RA, Tiller GE, and additional individual...
Science. 2017 Jan 20;355(6322):
Kim TH, Mehrabi P, Ren Z, Sljoka A, Ing C, Bezginov A, Ye L, Pomès R, Prosser RS, Pai EF
J Biomol Struct Dyn. 2016 Dec 29;:1-26
Chirgadze YN, Boshkova EA, Battaile KP, Mendes VG, Lam R, Chan TS, Romanov V, Pai EF, Chirgadze NY
Nat Commun. 2016;7:10882
Meyer PA, Socias S, Key J, Ransey E, Tjon EC, Buschiazzo A, Lei M, Botka C, Withrow J, Neau D, Rajashankar K, Anderson KS, Baxter RH, Blacklow SC, Boggon TJ, Bonvin AM, Borek D, Brett TJ, Caflisch A, Chang CI, Chazin WJ, Corbett KD, Cosgrove MS,...
PLoS One. 2016;11(3):e0149830
Kuo KH, Khan S, Rand ML, Mian HS, Brnjac E, Sandercock LE, Akula I, Julien JP, Pai EF, Chesney AE



Senior Scientist, Campbell Family Cancer Research Institute
Professor, Departments of Biochemistry, Medical Biophysics, and Molecular Genetics, University of Toronto
Canada Research Chair in Structural Biology​