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Department of Pharmacology

 

 

Prof. Hendrik W. van Veen - Group leader

E-mail: hwv20@cam.ac.uk

Tel: +44 1223 765295/334073
Fax: +44 1223 334100

 

Keywords

Research tackling antimicrobial resistance (AMR), inhibition of antibiotic resistance mechanisms (ARM), Clare College, drug resistance, antibiotic resistance, anticancer drug resistance, membrane transporters, multidrug transporters, drug efflux, molecular basis of drug recognition, mechanisms of transport, bioenergetics, inhibitors, electrophysiological & biochemical/biophysical assays.

 

Investigator biography

Hendrik van Veen earned his BSc and MSc degrees in Biochemistry, and PhD degree in Microbiology, at Wageningen University in the Netherlands. In 2001 he became associated with the Department of Pharmacology at Cambridge University, where he currently is a professor of molecular pharmacology, teaching fellow at Clare College, and principal investigator of a research group aiming at the mechanisms of antibiotic and anticancer drug recognition and transport by multidrug transporters in pro- and eukaryotic cells. He serves on various editorial boards and committees of funding agencies and societies. Click here for a citation overview of his publications.

 

Lab members

 

 

Our expertise

We focus on structure-function relationships in ABC (ATP binding cassette), MFS (major facilitator superfamily), and MATE (multidrug and toxic compound extrusion) multidrug transporters that underlie their ability to be polyspecific and mediate metabolic energy-dependent drug extrusion. The interaction of these transporters with ligands is analysed in transport measurements in intact cells, membrane vesicles, and proteoliposomes containing purified & reconstituted transport proteins. Ligand binding is also assessed in equilibrium binding assays with radiolabelled compounds, in fluorescence anisotropy and tryptophan fluorescence assays in detergent solutions, proteoliposomes, lipidic MSP1D1E nanodiscs and peptidiscs. For ABC transporters, ATPase measurements are also useful to examine the interaction of the transporters with their ligands. Electrophysiological techniques are used to study electrogenic substrate transport reactions in planar lipid bilayers and solid-supported membranes. Through collaborations with others, the group also includes molecular dynamics simulations, crystallographic and cryo-EM data, and NMR, EPR, and mass spectrometry data in their studies. We use a wide range of techniques to find answers to our scientific questions.

 

Selected publications

Van Veen, H.W., Venema, K., Bolhuis, B., Oussenko, I., Kok, J., Poolman, B., Driessen, A.J.M., and Konings, W.N. (1996) Multidrug resistance mediated by a bacterial homolog of the human drug transporter MDR1. Proc. Natl. Acad. Sci. USA 93: 10668-10672.

Van Veen, H.W., Callaghan, R., Soceneantu, L., Sardini, A., Konings, W.N., and Higgins, C.F. (1998) A bacterial antibiotic-resistance gene that complements the human multidrug-resistance P-glycoprotein gene. Nature 391: 291-295.

Putman, M., Koole, L., Van Veen, H.W., and Konings, W.N. (1999) The secondary multidrug transporter LmrP contains multiple drug interaction sites. Biochemistry 38: 13900-13905.

Van Veen, H.W., Margolles, A., Müller, M., Higgins, C.F., and Konings, W.N. (2000) The ATP-binding cassette transporter LmrA mediates multidrug transport by an alternating two-site (two-cylinder engine) mechanism. EMBO J. 19: 2503-2514.

Venter, H., Shilling, R., Velamakanni, S., Balakrishnan, L., and Van Veen, H.W. (2003) An ABC transporter with a secondary-active multidrug translocator domain. Nature 426: 866-869.

Reuter, G., Janvilisri, T., Venter, H., Shahi, S., Balakrishnan, L., and Van Veen, H.W. (2003) The ATP-binding cassette multidrug transporter LmrA and lipid transporter MsbA have overlapping substrate specificities. J. Biol. Chem 278: 35193-35198.

Balakrishnan, L., Venter, H., Shilling, R.A., and Van Veen, H.W. (2004) Reversible transport by the ATP-binding cassette multidrug export pump LmrA: ATP synthesis at the expense of downhill ethidium uptake. J. Biol. Chem. 279: 11273-11280.

Woebking, B., Velamakanni, S., Federici, L., Seeger, M.A., Murakami, S., and Van Veen, H.W. (2008) Functional role of transmembrane helix 6 in drug binding and transport by the ABC transporter MsbA. Biochemistry 47: 10904-10914.

Barrera, N.P., Isaacson, S.C., Zhou, M., Bavro, V.N., Welch, A., Schaedler, T.A., Seeger, M.A., Miguel, R.N., Korkhov, V.M., van Veen, H.W., Venter, H., Walmsley, A.R., Tate, C.G., Robinson, C.V. (2009) Mass spectrometry of membrane transporters reveals subunit stoichiometry and interactions. Nature Methods 6(8):585-587.

Van Veen, H.W. (2010) Structural biology: Last of the multidrug transporters. Nature 467: 926-927.

Schaedler, T.A., and Van Veen, H.W. (2010) A flexible cation binding site in the multidrug major facilitator superfamily transporter LmrP is associated with variable proton coupling. FASEB J. 24: 3653-3661.

Doshi, R., Ali, A., Shi, W., Freeman, E.V., Fagg, L.A., van Veen, H.W. (2013) Molecular disruption of the power stroke in the ATP-binding cassette transport protein MsbA. J Biol Chem. 288(10):6801-6813.

Choudhury*, H.G., Tong*, Z., Mathavan, I., Li, Y., Iwata, S., Zirah, S., Rebuffat, S., Van Veen, H.W., and Beis, K. (2014) Structure of an antibacterial peptide ATP-binding cassette transporter in a novel outward occluded state. Proc. Natl. Acad. Sci. USA. 111: 9145-9150. (* shared first authors)

Jin, Y., Nair, A., and Van Veen, H.W. (2014) Multidrug transport protein NorM from Vibrio cholerae simultaneously couples to sodium- and proton-motive force. J. Biol. Chem. 289(21): 14624-14632

Singh, H., Velamakanni, S., Deery, M.J., Howard, J., Wei, S.L., and Van Veen, H.W. (2016) ATP-dependent substrate transport by the ABC transporter MsbA is proton-coupled. Nature Commun. 7, 12387 doi: 10.1038/ncomms12387.

Fitzpatrick, A. W. P., Llabrés, S., Neuberger, A., Blaza, J.N., Bai, X.C., Okada, U., Murakami, S., van Veen, H.W., Zachariae, U., Scheres, S.H.W., Luisi, B.F., Du, D. (2017) Structure of the MacAB-TolC ABC-type tripartite multidrug efflux pump. Nature Microbiol. 2:17070. doi: 10.1038/nmicrobiol.2017.70.

Okada, U., Yamashita, E., Neuberger, A., Morimoto, M., van Veen, H.W., Murakami, S. (2017) Crystal structure of tripartite-type ABC transporter MacB from Acinetobacter baumannii. Nature Commun. 8(1):1336.   doi: 10.1038/ s41467-017-01399-2.

Du, D., Wang-Kan, X., Neuberger, A., van Veen, H.W., Pos, K.M., Piddock, L.J.V., Luisi, B.F. (2018) Multidrug efflux pumps: structure, function and regulation. Nature Reviews Microbiol. 16(9):523-539. doi: 10.1038/s41579-018-0048-6.

Agboh, K., Lau, C.H.F., Khoo, Y.S.K., Singh, H., Raturi, S., Nair, A.V., Howard, J., Chiapello, M., Feret, R., Deery, M.J., Murakami, S., van Veen, H.W. (2018) Powering the ABC multidrug exporter LmrA: How nucleotides embrace the ion-motive force. Science Advances 4, eaas9365.

Raturi, S., Nair, A. V., Shinoda, K., Singh, H., Bai, B., Murakami, S., Fujitani, H., van Veen, H. W. (2021) Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae. Commun. Biol. 4: 558.

Guffick, C., Hsieh, P.,-Y., Ali, A., Shi, W., Howard, J., Chinthapalli, D.K., Kong, A.C., Salaa, I., Crouch, L.I., Ansbro, M.R., Isaacson, S.C., Singh, H., Barrera, N.P., Nair, A.V., Robinson, C.V., Deery, M.J., van Veen, H.W. (2022) Drug-dependent inhibition of nucleotide hydrolysis in the heterodimeric ABC multidrug transporter PatAB from Streptococcus pneumoniae. FEBS J. 289: 3770-3788. doi: 10.1111/febs.16366. PMID: 35066976

Guo, D., Singh, H., Shimoyama, A., Guffick, C., Tang, Y., Rowe, S.M., Noel, T., Spring, D.R., Fukase, K., van Veen, H.W. (2022) Energetics of lipid transport by the ABC transporter MsbA is lipid dependent. Commun Biol. 4(1):1379. doi: 10.1038/s42003-021-02902-8. PMID: 34887543