Robert Fletterick, PhD

Professor
Biochemistry and BIophysics
+1 415 463-7452

Robert Fletterick is in the Department of Biochemistry at the University of California, San Francisco where he has served as Chair and Vice Chair.  He is also jointly appointed with the Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology at UCSF.  Robert is a world-renowned researcher in the area of structural biology.  His laboratory has determined high-resolution X-ray crystal structures of nuclear receptors, kinesin molecular motors, clathrin, and many enzymes.  He is known for his work on constructing engineered proteins with new function. For about ten years from 1975-1985, the structures of glycogen phosphorylase determined in his lab were record holders. Glycogen phosphorylase, which controls glucose metabolism but knowing when to degrade glycogen to feed the glycolytic pathway, was the largest molecule imaged by X-ray crystallography. Robert Fletterick’s laboratory solved the first structure of a nuclear receptor bound to its hormone and the first structure of the molecular motor kinesin found in nerve cells, showing it related to the well known myosin motor protein of muscle. Presently his lab studies hormone receptors that regulate embryogenesis, steroid metabolism and prostate development and cancer.
Robert received his Ph.D. from Cornell University and did his postdoctoral research in molecular biophysics in the laboratory of Dr. Thomas Steitz at Yale University.  Before settling at UCSF, Robert was a professor of Biochemistry at the University of Alberta, and a founding member of the MRC Group on Protein Structure and Function. He has coauthored over two hundred eighty basic science papers.

Dr. Fletterick was elected to the National Academy of Sciences, April 2010.

Publications: 

Development of 5N-Bicalutamide, a High-Affinity Reversible Covalent Antiandrogen.

ACS chemical biology

de Jesus Cortez F, Nguyen P, Truillet C, Tian B, Kuchenbecker KM, Evans MJ, Webb P, Jacobson MP, Fletterick RJ, England PM

NR5A2 discovering compounds that block tumor growth in PDAC.

Journal of surgical oncology

Fletterick R

Disulfide-Trapping Identifies a New, Effective Chemical Probe for Activating the Nuclear Receptor Human LRH-1 (NR5A2).

PloS one

de Jesus Cortez F, Suzawa M, Irvy S, Bruning JM, Sablin E, Jacobson MP, Fletterick RJ, Ingraham HA, England PM

Dlx5 Homeodomain:DNA Complex: Structure, Binding and Effect of Mutations Related to Split Hand and Foot Malformation Syndrome.

Journal of molecular biology

Proudfoot A, Axelrod HL, Geralt M, Fletterick RJ, Yumoto F, Deacon AM, Elsliger MA, Wilson IA, Wüthrich K, Serrano P

A gene-expression screen identifies a non-toxic sumoylation inhibitor that mimics SUMO-less human LRH-1 in liver.

eLife

Suzawa M, Miranda DA, Ramos KA, Ang KK, Faivre EJ, Wilson CG, Caboni L, Arkin MR, Kim YS, Fletterick RJ, Diaz A, Schneekloth JS, Ingraham HA

Structure of Liver Receptor Homolog-1 (NR5A2) with PIP3 hormone bound in the ligand binding pocket.

Journal of structural biology

Sablin EP, Blind RD, Uthayaruban R, Chiu HJ, Deacon AM, Das D, Ingraham HA, Fletterick RJ

The FKBP52 Cochaperone Acts in Synergy with ß-Catenin to Potentiate Androgen Receptor Signaling.

PloS one

Storer Samaniego C, Suh JH, Chattopadhyay A, Olivares K, Guy N, Sivils JC, Dey P, Yumoto F, Fletterick RJ, Strom AM, Gustafsson JÅ, Webb P, Cox MB

Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells.

Proceedings of the National Academy of Sciences of the United States of America

Hayashi Y, Caboni L, Das D, Yumoto F, Clayton T, Deller MC, Nguyen P, Farr CL, Chiu HJ, Miller MD, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Tomoda K, Conklin BR, Wilson IA, Yamanaka S, Fletterick RJ

Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism.

Nature communications

Torres IO, Kuchenbecker KM, Nnadi CI, Fletterick RJ, Kelly MJ, Fujimori DG

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs.

Proceedings of the National Academy of Sciences of the United States of America

Bayrer JR, Mukkamala S, Sablin EP, Webb P, Fletterick RJ

Advances in our structural understanding of orphan nuclear receptors.

Trends in biochemical sciences

Gallastegui N, Mackinnon JA, Fletterick RJ, Estébanez-Perpiñá E

The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1.

Proceedings of the National Academy of Sciences of the United States of America

Blind RD, Sablin EP, Kuchenbecker KM, Chiu HJ, Deacon AM, Das D, Fletterick RJ, Ingraham HA

Computer modeling of a newly identified THRB gene mutation (S350L) associated with resistance to thyroid hormone in three unrelated patients.

Thyroid : official journal of the American Thyroid Association

Nagavalli S, Fletterick RJ, Ford G, Boston BA, Gianoukakis AG

The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable.

PloS one

Benod C, Villagomez R, Filgueira CS, Hwang PK, Leonard PG, Poncet-Montange G, Rajagopalan S, Fletterick RJ, Gustafsson JÅ, Webb P

Structural and functional insight into TAF1-TAF7, a subcomplex of transcription factor II D.

Proceedings of the National Academy of Sciences of the United States of America

Bhattacharya S, Lou X, Hwang P, Rajashankar KR, Wang X, Gustafsson JÅ, Fletterick RJ, Jacobson RH, Webb P

Incidental identification of a thyroid hormone receptor beta (THRB) gene variant in a family with autoimmune thyroid disease.

Thyroid : official journal of the American Thyroid Association

Larsen CC, Dumitrescu A, Guerra-Argüero LM, Gállego-Suárez C, Vazquez-Mellado A, Vinogradova M, Fletterick R, Refetoff S, Weiss RE

Plant Kinesin-Like Calmodulin Binding Protein Employs Its Regulatory Domain for Dimerization.

PloS one

Vinogradova MV, Malanina GG, Waitzman JS, Rice SE, Fletterick RJ

Structure-based discovery of antagonists of nuclear receptor LRH-1.

The Journal of biological chemistry

Benod C, Carlsson J, Uthayaruban R, Hwang P, Irwin JJ, Doak AK, Shoichet BK, Sablin EP, Fletterick RJ

Structure of a novel winged-helix like domain from human NFRKB protein.

PloS one

Kumar A, Möcklinghoff S, Yumoto F, Jaroszewski L, Farr CL, Grzechnik A, Nguyen P, Weichenberger CX, Chiu HJ, Klock HE, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Conklin BR, Fletterick RJ, Wilson IA

Structural basis of coactivation of liver receptor homolog-1 by ß-catenin.

Proceedings of the National Academy of Sciences of the United States of America

Yumoto F, Nguyen P, Sablin EP, Baxter JD, Webb P, Fletterick RJ

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation.

Proceedings of the National Academy of Sciences of the United States of America

Benod C, Vinogradova MV, Jouravel N, Kim GE, Fletterick RJ, Sablin EP

A conserved surface on the ligand binding domain of nuclear receptors for allosteric control.

Molecular and cellular endocrinology

Buzón V, Carbó LR, Estruch SB, Fletterick RJ, Estébanez-Perpiñá E

Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells.

Proceedings of the National Academy of Sciences of the United States of America

De Leon JT, Iwai A, Feau C, Garcia Y, Balsiger HA, Storer CL, Suro RM, Garza KM, Lee S, Kim YS, Chen Y, Ning YM, Riggs DL, Fletterick RJ, Guy RK, Trepel JB, Neckers LM, Cox MB

Decoration of microtubules in solution by the kinesin-14, Ncd.

Acta crystallographica. Section D, Biological crystallography

Hjelm RP, Stone DB, Fletterick RJ, Mendelson RA

Conformation switching of clathrin light chain regulates clathrin lattice assembly.

Developmental cell

Wilbur JD, Hwang PK, Ybe JA, Lane M, Sellers BD, Jacobson MP, Fletterick RJ, Brodsky FM

Accommodation of structural rearrangements in the huntingtin-interacting protein 1 coiled-coil domain.

Acta crystallographica. Section D, Biological crystallography

Wilbur JD, Hwang PK, Brodsky FM, Fletterick RJ

Structure of the complex of a mitotic kinesin with its calcium binding regulator.

Proceedings of the National Academy of Sciences of the United States of America

Vinogradova MV, Malanina GG, Reddy AS, Fletterick RJ

Molecular basis for dimer formation of TRbeta variant D355R.

Proteins

Jouravel N, Sablin E, Togashi M, Baxter JD, Webb P, Fletterick RJ

The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1.

Proceedings of the National Academy of Sciences of the United States of America

Sablin EP, Woods A, Krylova IN, Hwang P, Ingraham HA, Fletterick RJ

Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands.

Molecular endocrinology (Baltimore, Md.)

Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ, Ingraham HA

6-Azido-7-nitro-1,4-dihydroquinoxaline-2,3-dione (ANQX) forms an irreversible bond to the active site of the GluR2 AMPA receptor.

Journal of medicinal chemistry

Cruz LA, Estébanez-Perpiñá E, Pfaff S, Borngraeber S, Bao N, Blethrow J, Fletterick RJ, England PM

Actin binding by Hip1 (huntingtin-interacting protein 1) and Hip1R (Hip1-related protein) is regulated by clathrin light chain.

The Journal of biological chemistry

Wilbur JD, Chen CY, Manalo V, Hwang PK, Fletterick RJ, Brodsky FM

Structural dynamics of the microtubule binding and regulatory elements in the kinesin-like calmodulin binding protein.

Journal of structural biology

Vinogradova MV, Malanina GG, Reddy VS, Reddy AS, Fletterick RJ

Interaction between the androgen receptor and a segment of its corepressor SHP.

Acta crystallographica. Section D, Biological crystallography

Jouravel N, Sablin E, Arnold LA, Guy RK, Fletterick RJ

Inhibitors of the interaction of a thyroid hormone receptor and coactivators: preliminary structure-activity relationships.

Journal of medicinal chemistry

Arnold LA, Kosinski A, Estébanez-Perpiñá E, Fletterick RJ, Guy RK

A surface on the androgen receptor that allosterically regulates coactivator binding.

Proceedings of the National Academy of Sciences of the United States of America

Estébanez-Perpiñá E, Arnold LA, Arnold AA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P, Fletterick RJ

Perspectives on designs of antiandrogens for prostate cancer.

Expert opinion on drug discovery

Estébanez-Perpiñá E, Jouravel N, Fletterick RJ

Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor.

Molecular endocrinology (Baltimore, Md.)

Estébanez-Perpiñá E, Arnold LA, Jouravel N, Togashi M, Blethrow J, Mar E, Nguyen P, Phillips KJ, Baxter JD, Webb P, Guy RK, Fletterick RJ

The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family.

Structure (London, England : 1993)

Wang SX, Pandey KC, Scharfstein J, Whisstock J, Huang RK, Jacobelli J, Fletterick RJ, Rosenthal PJ, Abrahamson M, Brinen LS, Rossi A, Sali A, McKerrow JH

Ca ion and the troponin switch.

Advances in experimental medicine and biology

Vinogradova MV, Stone DB, Malanina GG, Mendelson RA, Fletterick RJ

Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease.

Proceedings of the National Academy of Sciences of the United States of America

Wang SX, Pandey KC, Somoza JR, Sijwali PS, Kortemme T, Brinen LS, Fletterick RJ, Rosenthal PJ, McKerrow JH

Directed evolution of an anti-prion protein scFv fragment to an affinity of 1 pM and its structural interpretation.

Journal of molecular biology

Luginbühl B, Kanyo Z, Jones RM, Fletterick RJ, Prusiner SB, Cohen FE, Williamson RA, Burton DR, Plückthun A

A high-throughput screening method to identify small molecule inhibitors of thyroid hormone receptor coactivator binding.

Science's STKE : signal transduction knowledge environment

Arnold LA, Estébanez-Perpiñá E, Togashi M, Shelat A, Ocasio CA, McReynolds AC, Nguyen P, Baxter JD, Fletterick RJ, Webb P, Guy RK

An atomic model of the thin filament in the relaxed and Ca2+-activated states.

Journal of molecular biology

Pirani A, Vinogradova MV, Curmi PM, King WA, Fletterick RJ, Craig R, Tobacman LS, Xu C, Hatch V, Lehman W

Dynamics of the C-terminal region of TnI in the troponin complex in solution.

Biophysical journal

Blumenschein TM, Stone DB, Fletterick RJ, Mendelson RA, Sykes BD

Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators.

The Journal of biological chemistry

Arnold LA, Estébanez-Perpiñá E, Togashi M, Jouravel N, Shelat A, McReynolds AC, Mar E, Nguyen P, Baxter JD, Fletterick RJ, Webb P, Guy RK

Calcium-dependent changes in the flexibility of the regulatory domain of troponin C in the troponin complex.

The Journal of biological chemistry

Blumenschein TM, Stone DB, Fletterick RJ, Mendelson RA, Sykes BD

Ca(2+)-regulated structural changes in troponin.

Proceedings of the National Academy of Sciences of the United States of America

Vinogradova MV, Stone DB, Malanina GG, Karatzaferi C, Cooke R, Mendelson RA, Fletterick RJ

Conformational adaptation of nuclear receptor ligand binding domains to agonists: potential for novel approaches to ligand design.

The Journal of steroid biochemistry and molecular biology

Togashi M, Borngraeber S, Sandler B, Fletterick RJ, Webb P, Baxter JD

Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1.

Cell

Krylova IN, Sablin EP, Moore J, Xu RX, Waitt GM, MacKay JA, Juzumiene D, Bynum JM, Madauss K, Montana V, Lebedeva L, Suzawa M, Williams JD, Williams SP, Guy RK, Thornton JW, Fletterick RJ, Willson TM, Ingraham HA

The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor.

The Journal of biological chemistry

Estébanez-Perpiñá E, Moore JM, Mar E, Delgado-Rodrigues E, Nguyen P, Baxter JD, Buehrer BM, Webb P, Fletterick RJ, Guy RK

Thyroxine-thyroid hormone receptor interactions.

The Journal of biological chemistry

Sandler B, Webb P, Apriletti JW, Huber BR, Togashi M, Cunha Lima ST, Juric S, Nilsson S, Wagner R, Fletterick RJ, Baxter JD

Recognition and accommodation at the androgen receptor coactivator binding interface.

PLoS biology

Hur E, Pfaff SJ, Payne ES, Grøn H, Buehrer BM, Fletterick RJ

Structure of a kinesin microtubule depolymerization machine.

The EMBO journal

Shipley K, Hekmat-Nejad M, Turner J, Moores C, Anderson R, Milligan R, Sakowicz R, Fletterick R

Crystal structure of kinesin regulated by Ca(2+)-calmodulin.

The Journal of biological chemistry

Vinogradova MV, Reddy VS, Reddy AS, Sablin EP, Fletterick RJ

Coordination between motor domains in processive kinesins.

The Journal of biological chemistry

Sablin EP, Fletterick RJ

Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor.

Proceedings of the National Academy of Sciences of the United States of America

Borngraeber S, Budny MJ, Chiellini G, Cunha-Lima ST, Togashi M, Webb P, Baxter JD, Scanlan TS, Fletterick RJ

The extended interactions and Gla domain of blood coagulation factor Xa.

Biochemistry

Wang SX, Hur E, Sousa CA, Brinen L, Slivka EJ, Fletterick RJ

The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity.

Nature structural biology

Bell JK, Goetz DH, Mahrus S, Harris JL, Fletterick RJ, Craik CS

Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1.

Molecular cell

Sablin EP, Krylova IN, Fletterick RJ, Ingraham HA

Two resistance to thyroid hormone mutants with impaired hormone binding.

Molecular endocrinology (Baltimore, Md.)

Huber BR, Sandler B, West BL, Cunha Lima ST, Nguyen HT, Apriletti JW, Baxter JD, Fletterick RJ

Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain.

Molecular endocrinology (Baltimore, Md.)

Huber BR, Desclozeaux M, West BL, Cunha-Lima ST, Nguyen HT, Baxter JD, Ingraham HA, Fletterick RJ

Design of thyroid hormone receptor antagonists from first principles.

The Journal of steroid biochemistry and molecular biology

Webb P, Nguyen NH, Chiellini G, Yoshihara HA, Cunha Lima ST, Apriletti JW, Ribeiro RC, Marimuthu A, West BL, Goede P, Mellstrom K, Nilsson S, Kushner PJ, Fletterick RJ, Scanlan TS, Baxter JD

Two conformations in the human kinesin power stroke defined by X-ray crystallography and EPR spectroscopy.

Nature structural biology

Sindelar CV, Budny MJ, Rice S, Naber N, Fletterick R, Cooke R

Phosphorylation and intramolecular stabilization of the ligand binding domain in the nuclear receptor steroidogenic factor 1.

Molecular and cellular biology

Desclozeaux M, Krylova IN, Horn F, Fletterick RJ, Ingraham HA

Structure of an F-actin trimer disrupted by gelsolin and implications for the mechanism of severing.

The Journal of biological chemistry

Dawson JF, Sablin EP, Spudich JA, Fletterick RJ

How does ATP hydrolysis control actin's associations?

Proceedings of the National Academy of Sciences of the United States of America

Sablin EP, Dawson JF, VanLoock MS, Spudich JA, Egelman EH, Fletterick RJ

Structure-activity analysis of the purine binding site of human liver glycogen phosphorylase.

Chemistry & biology

Ekstrom JL, Pauly TA, Carty MD, Soeller WC, Culp J, Danley DE, Hoover DJ, Treadway JL, Gibbs EM, Fletterick RJ, Day YS, Myszka DG, Rath VL

Computer-assisted mutagenesis of ecotin to engineer its secondary binding site for urokinase inhibition.

The Journal of biological chemistry

Laboissière MC, Young MM, Pinho RG, Todd S, Fletterick RJ, Kuntz I, Craik CS

Structure-based design and synthesis of a thyroid hormone receptor (TR) antagonist.

Endocrinology

Baxter JD, Goede P, Apriletti JW, West BL, Feng W, Mellstrom K, Fletterick RJ, Wagner RL, Kushner PJ, Ribeiro RC, Webb P, Scanlan TS, Nilsson S

TR surfaces and conformations required to bind nuclear receptor corepressor.

Molecular endocrinology (Baltimore, Md.)

Marimuthu A, Feng W, Tagami T, Nguyen H, Jameson JL, Fletterick RJ, Baxter JD, West BL