Graduate Program Information
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Emeritus Professor of Biochemistry and Biophysics
Ph.D. Newcastle upon Tyne (England) 1968

(1) Multidrug resistance in cancer. Cancer chemotherapy often fails because the tumor develops resistance to multiple drugs simultaneously. The culprit is multidrug-resistance protein (mdr) also known as P-glycoprotein. It is located in plasma membranes, and uses ATP to transport drugs out of cells. We have generated a cell line which greatly overexpresses mdr, from which enriched plasma membranes and purified protein are readily obtained. The long-term goal is to learn ways to disable or circumvent mdr protein in cancer cells.

(2) ATP synthesis and hydrolysis in F1Fo-ATP synthase. ATP synthase is the smallest known rotary motor. It uses subunit rotation to drive ATP synthesis, and ATP hydrolysis to drive subunit rotation. The subunit rotation is linked in turn to utilization or generation of a membrane proton gradient. We are using a variety of probes to study the mechanism of catalysis and to elucidate the molecular linkage between catalysis and subunit rotation. We use the E. coli enzyme and a range of molecular genetics, biochemical and biophysical techniques. In recent work we have focussed on application of fluoroscent probes of cataytic sites which have yielded rapid and sensitive information about mechanism.

The catalytic site transition state complex for ATP hydrolysis and synthesis in ATP synthase. Deduced from studies using inserted tryptophan fluorescent probes, catalytic site mutations, enzyme activity assays, and drawing upon the X-ray structure. (From Nadanaciva S. et al., (1999) Biochemistry 38, 15493-15499.)

Recent Publications

Senior AE (2007) ATP synthase: motoring to the finish line. Cell, 130:220-1

Carrier I, Urbatsch IL, Senior AE, Gros P (2007) Mutational analysis of conserved aromatic residues in the A-loop of the ABC transporter ABCB1A (mouse Mdr3). FEBS Lett, 581:301-8

Ahmad Z, Senior AE (2006) Inhibition of the ATPase activity of Escherichia coli ATP synthase by magnesium fluoride. FEBS Lett, 580:517-20

Tombline G, Urbatsch IL, Virk N, Muharemagic A, White LB, Senior AE (2006) Expression, purification, and characterization of cysteine-free mouse P-glycoprotein. Arch Biochem Biophys, 445:124-8

Senior AE, Muharemagi Cacute A, Wilke-Mounts S (2006) Assembly of the Stator in Escherichia coli ATP Synthase. Complexation of alpha Subunit with Other F(1) Subunits Is Prerequisite for delta Subunit Binding to the N-Terminal Region of alpha. Biochemistry, 45:15893-15902

Wilkens S, Borchardt D, Weber J, Senior AE (2005) Structural characterization of the interaction of the delta and alpha subunits of the Escherichia coli F1F0-ATP synthase by NMR spectroscopy. Biochemistry, 44:11786-94

Tombline G, Muharemagic A, White LB, Senior AE (2005) Involvement of the "occluded nucleotide conformation" of P-glycoprotein in the catalytic pathway. Biochemistry, 44:12879-86

Delannoy S, Urbatsch IL, Tombline G, Senior AE, Vogel PD (2005) Nucleotide Binding to the Multidrug Resistance P-Glycoprotein as Studied by ESR Spectroscopy. Biochemistry, 44:14010-14019

Ahmad Z, Senior AE (2005) Modulation of charge in the phosphate binding site of Escherichia coli ATP synthase. J Biol Chem, 280:27981-9

Ahmad Z, Senior AE (2005) Involvement of ATP synthase residues alphaArg-376, betaArg-182, and betaLys-155 in Pi binding. FEBS Lett, 579:523-8

Ahmad Z, Senior AE (2004) Role of betaAsn-243 in the phosphate-binding subdomain of catalytic sites of Escherichia coli F(1)-ATPase. J Biol Chem, 279:46057-64

Tombline G, Bartholomew LA, Tyndall GA, Gimi K, Urbatsch IL, Senior AE (2004) Properties of P-glycoprotein with mutations in the "catalytic carboxylate" glutamate residues. J Biol Chem, 279:46518-26

Weber J, Wilke-Mounts S, Nadanaciva S, Senior AE (2004) Quantitative determination of direct binding of b subunit to F1 in Escherichia coli F1F0-ATP synthase. J Biol Chem, 279:11253-8

Weber J, Muharemagic A, Wilke-Mounts S, Senior AE (2004) Analysis of Sequence Determinants of F1Fo-ATP Synthase in the N-terminal Region of alpha Subunit for Binding of delta Subunit. J Biol Chem, 279:25673-9

Ahmad Z, Senior AE (2004) Mutagenesis of residue betaArg-246 in the phosphate-binding subdomain of catalytic sites of Escherichia coli F1-ATPase. J Biol Chem, 279:31505-13

Tombline G, Bartholomew LA, Urbatsch IL, Senior AE (2004) Combined mutation of catalytic glutamate residues in the two nucleotide binding domains of P-glycoprotein generates a conformation that binds ATP and ADP tightly. J Biol Chem, 279:31212-20

Tombline G, Bartholomew L, Gimi K, Tyndall GA, Senior AE (2004) Synergy between conserved ABC signature Ser residues in P-glycoprotein catalysis. J Biol Chem, 279:5363-73

Senior AE, Weber J (2004) Happy motoring with ATP synthase. Nat Struct Mol Biol, 11:110-2

Weber J, Senior AE (2004) Fluorescent probes applied to catalytic cooperativity in ATP synthase. Methods Enzymol, 380:132-52

Contact Information

E-Mail: Alan_Senior@urmc.rochester.edu

Alan Senior
Department of Biochemistry and Biophysics
University of Rochester School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester, New York 14642

Office: Medical Center G-6804
Telephone: (585) 275-6645; Fax: (585) 271-2683