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structural biology and dynamics of these proteins and are working on discovery of small molecule and antibody binders against, as well as expanding our list of targets to include different families of fatty acid transporters with overlapping functionality to pinpoint mechanisms of substrate specificity. This project has been funded in part by an ongoing R01 grant (PI: Alam) from the NIH Institute of general medical sciences, and a grant from the United Leukodystrophy Foundation.
Mechanisms of Drug Efflux by P-Glycoprotein.
This project centers on mechanisms of substrate transport and regulation of the multidrug efflux pump p-glycoprotein (also known as MDR1 or ABCB1).
This protein carries immense clinical and pharmaco- logical relevance for its role in cellular detoxifications, mediation of chemotherapy resistance in cancer cells, and influence on drug-drug and drug-natural product interactions, and limiting drug bioavailability. As a result, it is listed as a primary counter screening
transporter in the FDA’s guidance for all developmen- tal drugs. Our group had determined several new structures of human ABCB1 in complex with substrates and inhibitors.
ORCID iD: https://orcid.org/0000-0001-9580-4949
Picture of the Alam lab (summer 2022).
From left: Phuoc Dang (Researcher 1),
Dr. Amer Alam (PI),
Dr. Le Thi My Le (Postdoc), Dr. Devanshu Kurre (Postdoc), and Jonah Forsyth (SURE intern)
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Cryo-EM Structure of human ABCA7 (purple) in complex with
a novel single chain variable fragment (scFv, Red) discovered in the Alam lab using a naïve scFv library obtained from the group of Dr. Aaron Lebeau at UW Madison. ECD=Extracellular Domain,
NBD = Nucleotide binding domain, RD = Regulatory Domain,
TMD = transmembrane Domain
PUBLICATION HIGHLIGHTS:
• Le, L. T. M., Thompson, J. R., Dehghani- Ghahnaviyeh, S., Pant, S., Dang, P. X., French, J. B., Kanikeyo, T., Tajkhorshid, E., & Alam, A. (2023). Cryo-EM structures of human ABCA7 provide insights into its phospholipid translocation mechanisms. EMBO Journal, 42(3), 14.
• Alam, A., & Locher, K. P. (2023). Structure and Mechanism of Human ABC Transporters. Annual Review of Biophysics, 52, 275-300.