Significant Papers


Troponin / Calcium Control of Muscle

Vinogradova MV, Stone DB, Malanina GG, Karatzaferi C, Cooke R, Mendelson RA, Fletterick RJ. (2005) Ca2+-regulated structural changes in troponin. PNAS U S A. 102(14): 5038-43.


Orphan Nuclear Receptors

Krylova I, Sablin EP, Moore J,  Xu RX, Waitt GM, McKay A., Juzumiene D, Bynum JM, Montana V, Lebedeva L, Suzawa M, Williams JD, Williams SP, Guy RK, Thornton JW, Fletterick RJ,Willson TM, and HA Ingraham. (2005) Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120: 343-355.

Jouravel N, Sablin E, Arnold LA, Guy RK and RJ Fletterick. (2007)  Interaction between the androgen receptor and a segment of its corepressors SHP. Acta Crystallogr D Biol Crystallogr. 63(Pt 11): 1198-1200.


Nuclear Receptors

Arnold LA, Kosinski A, Estébanez-Perpiñá E., Fletterick RJ, and RK Guy. (2007) Inhibitors of the interaction of a thyroid hormone receptor and coactivators: Preliminary structure-activity relationships. J Medicinal Chemistry 50(22): 5269-80.

Estébanez-Perpiñá, E., Jouravel, N., Arnold, L.A., Togashi, M., Mar, E., Sablin, E., Nguyen, P., R. Baxter, J.D., Webb, P., Guy, R. K. and Fletterick, R.J. (2007) Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor.  Molecular Endocrinology (12): 2919-28.

Estébanez-Perpiñá, E., Arnold A, Nguyen P, Rodriguez E, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P and RJ Fletterick.  (2007) A surface on the androgen receptor that allosterically regulates coactivator binding. Proc Natl Acad Sci USA (PNAS) 104(41):16074-9.

Arnold LA, Estebanez-Perpina E, Togashi M, Shelat A, Ocasio CA, McReynolds AC, Nguyen P, Baxter JD, Fletterick RJ, Webb P, Guy RK. (2006) A high-throughput screening method to identify small molecule inhibitors of thyroid hormone receptor coactivator binding. Sci STKE. Jun 27 (341):pl3.

Arnold LA, Estebanez-Perpina E, Togashi M, Jouravel N, Shelat A, McReynolds AC, Mar E, Nguyen P, Baxter JD, Fletterick RJ, Webb P, Guy RK. (2005)  Discovery of small molecule inhibitors of the interaction of thyroid hormone receptor with transcriptional coregulators. J Biol Chem. 280(52): 43048-55.

Darimont, B.D., Wagner, R.L., Apriletti, J.W., Stallcup, M.R., Kushner, P.J., Baxter, J.D., Fletterick, R.J., and K.R. Yamamoto.  (1998) Structure and specificity of nuclear receptor-coactivator interactions. Genes & Development 12: 3343-3356.

Feng, W., Ribeiro, R.C.J., Wagner, R.L., Nguyen, H., Apriletti, J.W., Fletterick, R.J., Baxter, J.D., Kushner, P.J., and B.L. West. (1998)  A hydrophobic surface cleft on nuclear receptors mediating hormone-dependent coactivator binding.  Science 280: 1747-1750.

Wagner, R.L., Apriletti, J.W., McGrath, M.E., West, B.L., Baxter, J.D., Fletterick, R.J. (1995)  A structural role for hormone in the thyroid hormone receptor.  Nature 378(6558): 670-697.


Clathrin Assembly

Ybe JA, Brodsky FM, Hofmann K, Lin K, Liu SH, Chen L, Earnest TN, Fletterick, RJ, Hwang PK.  (1999)  Clathrin self-assembly is mediated by a tandemly repeated superhelix.  Nature 399(6734): 371-5.


Actin Assembly

Sablin EP, Dawson JF, VanLoock MS, Spudich JA, Egelman EH, Fletterick RJ.  (2002) How does ATP hydrolysis control actin's associations?  Proc Natl Acad Sci U S A 99(17): 10945-7.


Kinesins / How Motors Move

Sindelar CV, Budny MJ, Rice S, Naber N, Fletterick R, and Cooke R.(2002) Two conformations in the human kinesin powerstroke defined by X-ray crystallography and EPR spectroscopy.  Nature Structural Biology 9(11): 844-8.

Kikkawa, M., Sablin, E.P., Okada, Y., Yajima, H., Fletterick R.J. and N. Hirokawa. (2001) Switch-based mechanism of kinesin motors. Nature 411(6836): 439-45

Sablin, E. P., Case, R.B., Dai, S.C., Hart, C.L., Ruby, A., Vale, R.D. and R.J. Fletterick (1998) Direction determination in NCD, a minus end directed kinesin motor. Nature 395(6704): 813-6.

Sablin, E.P., Kull, F.J., Cooke, R., Vale, R.D. and R.J. Fletterick.  (1996)  Crystal structure of the motor domain of the kinesin-related motor ncd  Nature 380: 555-559.

Kull, F.J., Sablin, E.P., Lau, R., Fletterick, R.J. and R.D. Vale.  (1996)  Crystal structure of the kinesin motor domain reveals a structural similarity to myosin. Nature 380: 550-555.


Luginbuhl B, Kanyo Z, Jones RM, Fletterick RJ, Prusiner SB, Cohen FE, Williamson RA, Burton DR, Pluckthun A. (2006) Directed Evolution of an Anti-prion Protein scFv Fragment to an Affinity of 1 pM and its Structural Interpretation.  J Mol Biol. Oct 13; 363(1): 75-97.

Cohen, F.E., Pan, K.-M., Huang, Z., Baldwin, M., Fletterick, R.J. and Prusiner, S.B.  (1994)  Structural clues to prion replication.  Science 264(5158): 530-1.

Gasset, M., Baldwin, M.A., Fletterick, R., and S.B. Prusiner.  (1993)  Perturbation of the secondary structure of the scrapie prion protein under conditions that alter infectivity.  Proc. Natl. Acad. Sci. USA  90(1):1-5.

Gasset, M., Baldwin, M., Lloyd, D., Gabriel, J.-M., Holtzman, D.M., Cohen, F., Fletterick, R., and S.B. Prusiner.  (1992) Predicted a-helical regions of the prion protein when synthesized as peptides form amyloid.  Proc. Natl. Acad. Sci. USA  89:10940-44.


Somoza, J.R., Chin, M.S., Focia, P.J., Wang, C.C., et al.  (1996)  Crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase from the protozoan parasite Tritrichomonas foetusBiochemistry 35(22): 7032-7040.

Craig, S.P., Focia, P.J. and R.J. Fletterick. (1997)  Substitution of lysine for arginine at position 199 of a hypoxanthine phosphoribosyltransferase interferes with binding of the primary substrate to the active site.  Biochim.Biophys.Acta  1339(1): 1-3.

Focia PJ; Craig SP 3rd; Nieves-Alicea R; Fletterick RJ; Eakin AE.  (1998)  A 1.4 A crystal structure for the hypoxanthine phosphoribosyltransferase of Trypanosoma cruzi.   Biochemistry  37(43): 15066-75.


Cruzain / Parasite Proteins as Drug Targets

Eakin, A., McGrath, M.E., McKerrow, J.H., Fletterick, R.J. and C.S. Craik. (1992) Production of crystallizable cruzain, the major cysteine protease from Trypanosoma cruzi. J. Biol. Chem  268(9):6115-8.

McGrath, M.E., Eakin, A.E., Engel, J.C., McKerrow, J.H., Craik, C.S. and R.J. Fletterick.  (1995)  The crystal structure of cruzain: A therapeutic target for Chagas' Disease.  J. Mol. Biol. 247: 251-259.

Wang SX, Pandey KC, Somoza JR, Sijwali PS, Kortemme T, Brinen LS, Fletterick RJ, Rosenthal PJ, McKerrow JH. (2006) Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease. Proc Natl Acad Sci U S A. 103(31):11503-8.

Ecotin and Protease Inhibition

Gillmor, S, Takeuchi, T., Yang, S.Q., Craik, C.S., and R.J. Fletterick.  (2000).  Compromise and accommodation in ecotin, a dimeric macromolecular inhibitor of serine proteases.  J. Molec. Biol.  299(4): 993-1003.

McGrath, M.E., Gillmor, S.A. and R.J. Fletterick.  (1995)  Ecotin:  Lessons on survival in a protease-filled world.  Protein Science 4:141-148.

McGrath, M.E., Erpel, T., Bystroff, C., and Fletterick, R.J.  (1994)  Macromolecular chelation as an improved mechanism of protease inhibition: Structure of the ecotin: trypsin complex.  EMBO J, 13(7):1502-1507.

McGrath, M.E., Hines, W.M., Sakanari, J.A., Fletterick, R.J., and C.S. Craik.  (1991)  The sequence and reactive site of ecotin:  A general inhibitor of pancreatic serine proteases from E. coliJ. Biol. Chem  266(10): 6620-6625.


Engineered Proteases and Enzyme Inhibition

Perona, John J., Craik, C.S. and Fletterick, R.J.  (1993)  Locating the catalytic water in serine proteases.  Science  261(5121): 620-622.

Higaki, J.N.,  Fletterick, R.J. and C.S. Craik (1992)  Engineered metalloregulation in enzymes.  TIBS 17(3): 100-104.

Higaki, J.N., Haymore, B.L., Chen, S., Fletterick, R.J., and Craik, C.S.   (1990)   The regulation of serine protease activity by a metal switch.  Biochem. 29: 8582-8586.

Yeast Glycogen Phosphorylase and Evolution of Control

Lin, K., Hwang, P.K. and R.J. Fletterick.  (1995)  Mechanism of regulation in yeast glycogen phosphorylase. J. Biol. Chem. 270(45): 26833-26839.

Rath, V.L., Lin, K., Hwang, P.K. and R.J. Fletterick. (1996)  The evolution of an allosteric site. Structure 4(4): 463-373.

Lin, K., Rath, V.L., Dai, S.C., Fletterick, R.J., and P.K. Hwang.  (1996) A protein phosphorylation switch at the conserved allosteric site in glycogen phosphorylase.  Science 273: 1539-1541.


Glycogen Phosphorylase and Phosphorylation Control

Sprang, S.R., Withers, S.G., Goldsmith, E.J., Fletterick, R.J., and N.B. Madsen  (1991)  The structural basis for the activation of glycogen phosphorylase b by AMP.  Science 254: 1367-1371.

Hwang, P.K., and Fletterick, R.J.  (1986)  Convergent and divergent evolution of regulatory sites in eukaryotic phosphorylases.  Nature 324: 80-84.

Sprang, S.R., Acharya, K.R., Goldsmith, E.J., Stuart, D.I., Varvill, K., Fletterick, R.J., Madsen, N.B., and Johnson, L.N.  (1988)  Structural changes in glycogen phosphorylase induced by phosphorylation.  Nature 336: 215-221.

Sprang, S., Goldsmith, E., and Fletterick, R.  (1987)  Structure of the nucleotide activation switch in glycogen phosphorylase aScience  237:  1012-1019.



McGrath, M.E., Haymore, B.L., Summers, N.L., Craik, C.S.,  and R.J. Fletterick.  (1993)  Structure of an engineered, metal-actuated switch in trypsin.  Biochemistry 32:1914-1919.

Perona, J.J., Tsu, C.A., McGrath, M.E., Craik, C.S. and R.J. Fletterick. (1992).  Relocating a negative charge in the binding pocket of trypsin.  J. Mol. Biol. 230:934-939.

Craik, C.S., Largman, C., Fletcher, T., Roczniak, S., Barr, P.J., Fletterick, R., and Rutter, W.J.  (1985)  Redesigning trypsin:  Alteration of substrate specificity.  Science 228: 291-297.