Molecules such as glucose, amino acids, nucleosides, and charged ions are essential for survival of cells but a large majority of them cannot penetrate the lipid bilayer. Transporters imbedded in the cellular membrane facilitate import or export of these molecules. Transporters have been studied for more than 60 years. However, the transport mechanism of most of these membrane proteins is still largely unknown due to many technical hurdles including expression, extraction, and crystallization.

To understand membrane transport processes, we use a large array of structural and biochemical approaches. The research tool we use is cryo-electron microscopy (cryo-EM). Using this technique we can determine atomic structures of transporters frozen in multiple conformational states. Several technical advances of electron microscopy in recent years revolutionized structural biology. First, the development of direct electron detection, second, the development of algorithms for data collection from imaging to classification and also for structural reconstruction, and third, the development of volta phase plate (VPP) for in-focus data collection. They solve a major challenge for structure determination of membrane proteins and have led to a rapid boom in the cryo-EM structure of various proteins ranging from 64 kDa to 150 MDa.

Our research focuses on the family of ATP-binding cassette (ABC) transporters that transport substrate across the cell membrane using ATP hydrolysis energy. The best known example of this is P-glycoprotein (P-gp).

P-gp is an ATP - dependent efflux pump that exports a structurally diverse array of hydrophobic drugs. Substrates bind to the inward-facing conformation in a cavity exposed to the cytoplasm and the membrane bilayer inner leaflet and are released in the outward-facing conformation in the presence of ATP binding. P-gp is an important target of anti-cancer drug discovery. Prolonged treatment of cancer often leads to resistance to multiple drugs. Overexpression of P-gp is commonly found multidrug resistant in cancer cells.

Therefore, the effectiveness of cancer chemotherapy treatment is often limited by overexpression of P-gp. Co-treatment of cancer chemotherapeutics with P-gp inhibitors has been shown to be effective in limiting drug resistance.
P-gp has been extensively studied for several decades, but biological questions still remain, such as how P-gp recognizes both cancer drug and P-gp inhibitor and how we can stop their outward-facing conformation changes enabling substrate transport across membranes. Our lab would like to study the substrate transport mechanism by a combination of biochemical and structural analysis including cryo-EM . These structural and functional studies will help in not only better understanding disease from transporters but also will help achieve better drug design and development for humans.

Another focus is on the group of solute carrier (SLC) transporters. Some SLC transporters are targets of drugs and they are being actively studied.
SLC transporters mediate influx or bidirectional movement of broad-ranged small substrates including inorganic ions, amino acids, lipids, sugars, neurotransmitters, and drugs. For example, neurotransmitter transporters are found in three distinct clusters: 1) The SLCl family, 2) the SLC6 and SLC32 families, and 3) the SLCl 7 and SLC18 families. The other SLC transporters, belonging to the same family, transport a different substrate and use a different mechanism (e.g. symporter vs antiporter). For many SLC transporter families, several crucial questions remain unanswered: 1) how they interact with specific substrate; and 2) how they control the cellular influx of substrates involving their conformational change.

Our lab would like to explain the molecular mechanism of SLC using the structural and biochemical tool cryo-EM.

• ㆍThe mechanism of membrane transporters
• ㆍCryo-electron microscopy
• ㆍX-ray crystallography

• ㆍKwon NY, Kim Yet al., (2018), Structural diversity and flexibility of diabodies. Methods, 154,136-142
• ㆍKim Yet al., (2018), Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science, 359(6378):915-919
• ㆍEckert JK, Kim VJ et al., (2013), The Crystal Structure of Lipopolysaccharide Binding Protein Reveals the Location of a Frequent Mutation that Impairs Innate Immunity. Immunity, 39, 1-14
• ㆍAn HJ, Kim VJ, Song DH et al., (2011), Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation. J. Biol. Chem, 286(13): 11226-11235

• ㆍB.S., Sungkyunkwan University, Suwon, Korea (2003)
• ㆍM.S., KAIST, Daejeon, Korea (2005)
• ㆍPh.D., KAIST, Daejeon, Korea (2011)

• ㆍ2011-2014 : Research associate, Dept. of Chemistry, KAIST
• ㆍ2014-2018 : Postdoctoral Fellow, The Rockefeller University, NY, USA
• ㆍ2018-2019 : Research associate, Dept. of Chemistry, KAIST
• ㆍ2019-Present : Assistant Professor, Dept. of Life Sciences, POSTECH