Since Dr. Yu began his tenure track position in 2004, he has developed a highly successful independent research program that focuses on the structure, assembly and mechanism of the resistance-nodulation-cell division (RND)-superfamily efflux pumps as well as the factors that regulate their expression. These efflux pumps are key components for Gram-negative pathogens to ensure their survival in toxic environments by extruding a variety of antimicrobial agents from bacterial cells. Typically, RND efflux pumps work in conjunction with a periplasmic membrane fusion protein and an outer membrane channel to form a functional protein complex. One such RND-type efflux system is the Escherichia coli CusCFBA tetrapartite heavy-metal efflux system, which specifically recognizes and confers resistance to Ag(I) and Cu(I) ions. Dr. Yu's lab has determined the crystal structures of the CusA heavy-metal efflux pump. We have also resolved the crystal structure of the CusBA adaptor-transporter efflux complex. This is the only adaptor-transporter efflux complex structure that has been determined using X-ray crystallography. In addition, they have determined two mutant structures of the CusC efflux channel, reviewing conformational changes accompanying folding and transmembrane channel formation of this outer membrane protein.
Ed Yu's lab has also elucidated the structure and function of the Burkholderia multivorans HpnN hopanoid transporter, a member of a subfamily of the RND-superfamily transporters. The HpnN membrane protein plays a predominant role in supporting membrane stability and barrier function, thus contributing to multidrug resistance. Having solved the structure of HpnN, he reasoned that they could develop compounds that block its function. Indeed, they have made considerable progress in this area and they are now in an excellent position to pursue the identification and function of novel peptides that are able to inhibit the function of this transporter. Because of the efflux pump works that Dr. Yu accomplished, he was invited to edit a book entitled “Microbial Efflux Pumps: Current Research” (Caister Academic Press, 2013).
Recently, they have developed a cryo-electron microscopy (Cryo-EM) methodology termed “Build and Retrieve” (BaR) that allows them to simultaneously solve structures of a variety of proteins from heterogeneous samples. The lab has successfully used BaR to determine structures from impure membrane fractions as well as from raw lysates from several tissues, including liver, kidney and brain. Coupled with other techniques such as proteomics and interactomics, the BaR methodology should help illuminate the details of biological networks at near atomic resolution. It is expected that in the future, cryo-EM will enable a new perspective on the elucidation of the human interactome at the atomic level.
1. F. Long, C.-C. Su, M.T. Zimmermann, S.E. Boyken, K.R. Rajashankar, R.L. Jernigan, and E.W. Yu. 2010. Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport. Nature. 467:484-488. PMCID: PMC2946090
2. C.-C. Su, F. Long, M.T. Zimmermann, K.R. Rajashankar, R.L. Jernigan, and E.W. Yu. 2011. Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli. Nature. 470:558-562. PMCID: PMC3078058
3. C.-C. Su, P.A. Klenotic, J.R. Bolla, G.E. Purdy, C.V. Robinson, E.W. Yu. 2019. MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine. Proc Natl Acad Sci USA. Jun 4;116(23):11241-11246. PMID: PMC31113875
4. C.-C. Su, M. Lyu, C.E. Morgan, J.R. Bolla, C.V. Robinson, E.W.Yu 2021. A 'Build and Retrieve' methodology to simultaneously solve cryo-EM structures of membrane proteins. Nat Methods. Jan;18(1):69-75. PMID: PMC33408407
5. M.A. Moseng, C.-C. Su, K. Rios, M. Cui, M. Lyu, P. Glaza, P.A. Klenotic, E. Delpire, E.W. Yu. 2022. Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling. Sci Adv. Oct 28;8(43) PMID: PMC36306358
7. Kumar, N., C.-C. Su, C.-C., T.-H. Chou, A. Radhakrishnan, J.A. Delmar, K.R. Rajashankar and E.W. Yu. 2017. Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN. Proc. Natl. Acad. Sci. USA 114:6557-6562. PMCID: PMC5488925
8. Su, C.-C., L. Yin, N. Kumar, L. Dai, A. Radhakrishnan, J. R. Bolla, H.-T. Lei, T.-H. Chou, J.A. Delmar, K. R. Rajashankar, Q. Zhang, Y.-K. Shin and E. W. Yu. 2017. Structures and transport dynamics of a multidrug efflux pump in Campylobacter jejuni. Nature Commun. 8:171. PMCID: PMC5537355