Christopher Hill, DPhil Research

We aim to understand the structural mechanistic basis for key pathways in a wide range of biology including HIV replication, protein quality control, and the regulation of chromatin. Our underlying premise is that because biology results from specific molecular interactions that are defined by atomic contacts, an effective approach to understanding how biological pathways work is to visualize the relevant molecules and their binding complexes in atomic detail. Structures are usually visualized using X-ray crystallography with biochemical experiments used to test mechanistic implications. We collaborate widely to test the biological relevance of mechanistic insights, especially with Wes Sundquist on questions of HIV biology, Tim Formosa and Brad Cairns on questions of chromatin regulation, and with Tim Formosa, Jared Rutter and others on questions of protein quality control.

Our studies have included determining the structure of proteins and interactions that define the architecture of the HIV virion 1-3 and interactions with cellular proteins that HIV recruits to escape from host cells 4-6. We also collaborate with Michael Kay on the development of novel inhibitors of HIV replication that have therapeutic potential 7. Our studies on the proteasome, which performs quality control and regulates many cellular pathways, have explained how all of the known activators use the same principles to open the gateway through which proteins must pass in order to be processed 8-10. Efforts to understand the regulation of chromatin have focused on the remodeling and reorganizing complexes that control the assembly and dynamics of nucleosomes, which form the fundamental unit of chromatin structure and are tightly regulated to enable access to DNA for processes such as replicating the genome, repairing damaged DNA, and expressing genes 11-14.

Molecular structures that explain how proteasomes are activated, reveal architecture at the core of chromatin remodeling complexes, and show interactions that HIV uses to escape from host cells.

Research Service Project: Enhancing Chemical Biology at the University of Utah

Chemical biology is the discovery and use of small molecules to understand and manipulate biology. It is a highly multidisciplinary approach that can discover new biological pathways and develop new diagnostic probes and therapeutics. It therefore offers considerable potential synergy with basic and translation efforts in multiple areas, including diabetes-metabolism, neuroscience, cancer biology, and immunology-infection-inflammation. The overall goal is to increase capability and promote collaborative opportunities between investigators located in multiple units across campus. Toward this end, I am working with a number of other researchers and administrators to obtain new chemical biology infrastructure and expertise.

Thus far we (with Jared Rutter, Wes Sundquist, and Dean Li) have secured USTAR funding to recruit new faculty members, strengthen the university core facility in drug discovery, and start a new university core facility in chemical synthesis. Last year we held a one-day symposium to learn more about the potential of chemical biology and meet 14 outstanding postdoctoral candidates interested in faculty positions, and held an international search for new faculty. We were delighted to recruit an outstanding new faculty member, Danny Chou, who stared as Assistant Professor of Biochemistry on August 1, 2014. Danny earned his PhD with Stuart Schreiber at Harvard University where he made seminal advances in identification, synthesis, and characterization of molecules that can protect pancreatic β cells from apoptosis. As a postdoctoral fellow with

Daniel Anderson and Robert Langer at MIT, Danny focused on designing novel glucose responsive insulin analogs (or “smart insulins”) that will require once daily or weekly injections to regulate blood glucose levels in diabetic patients. His independent research program will continue to develop insulin analogs and will expand into engineering other molecules that have the potential to dramatically improve the control of blood glucose levels. This research has a strong translational component and is highly synergistic with the division of endocrinology and the initiative in diabetes-obesity-metabolism.

Next year we will hold another one-day symposium and search for two new faculty members who will further strengthen chemical biology at the university and synergize with institutional priorities. I will also chair the search for a new Dean of the College of Pharmacy, which is a critical position for chemical biology and the University as a whole. Our goal is to build a world-leading community of chemical biologists who are pushing forward capability and fundamental understanding while developing practical, translational opportunities, and integrating with a comprehensive range of research programs at the university.

Biographical Summary

Education and Professional Experience: Undergraduate in Chemistry at the University of York (1977-80); D.Phil. in Chemistry with Guy Dodson at the University of York (1981-87); Postdoctoral Fellow in Structural Biology with David Eisenberg at UCLA (1988-91); Faculty Member in the University of Utah Department of Biochemistry (1992-present).

Current Professional Service: Co-Chair, Department of Biochemistry; Chair, NE-CAT (APS synchrotron) Scientific Advisory Board; Co-Chair, University of Utah Sustainability Advisory Board; Reviewing Editor, Journal of Biological Chemistry.

Honors and Awards: Dorothy Crowfoot Hodgkin Award from the Protein Society for exceptional contributions in protein science which profoundly influence our understanding of biology.

References

1 Gamble, T. R. et al. Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid. Cell 87, 1285-1294 (1996).

2 Gamble, T. R. et al. Structure of the carboxyl-terminal dimerization domain of the HIV-1 capsid protein. Science 278, 849-853 (1997).

3 Pornillos, O. et al. X-ray structures of the hexameric building block of the HIV capsid. Cell 137, 1282-1292 (2009). 4 Fisher, R. D. et al. Structural and biochemical studies of ALIX/AIP1 and its role in retrovirus budding. Cell 128, 841-

852 (2007). 5 Zhai, Q. et al. Structural and functional studies of ALIX interactions with YPX(n)L late domains of HIV-1 and EIAV.

Nature structural & molecular biology 15, 43-49 (2008). 6 McCullough, J. et al. ALIX-CHMP4 interactions in the human ESCRT pathway. Proc Natl Acad Sci USA 105, 7687-

7691 (2008). 7 Welch, B. D. et al. Potent D-peptide inhibitors of HIV-1 entry. Proc Natl Acad Sci USA 104, 16828-16833 (2007). 8 Whitby, F. G. et al. Structural basis for the activation of 20S proteasomes by 11S regulators. Nature 408, 115-120

(2000). 9 Forster, A. et al. The 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-

PAN/PA700 interactions. Molecular cell 18, 589-599 (2005). 10 Sadre-Bazzaz, K. et al. Structure of a Blm10 complex reveals common mechanisms for proteasome binding and gate

opening. Molecular cell 37, 728-735 (2010). 11 McDonald, S. M. et al. Structure and biological importance of the Spn1-Spt6 interaction, and its regulatory role in

nucleosome binding. Molecular cell 40, 725-735 (2010). 12 Schubert, H. L. et al. Structure of an actin-related subcomplex of the SWI/SNF chromatin remodeler. Proc Natl Acad

Sci. USA 110, 3345-3350 (2013). 13 VanDemark, A. P. et al. The structure of the yFACT Pob3-M domain, its interaction with the DNA replication factor

RPA, and a potential role in nucleosome deposition. Molecular cell 22, 363-374 (2006). 14 VanDemark, A. P. et al. Autoregulation of the rsc4 tandem bromodomain by gcn5 acetylation. Molecular cell 27, 817-

828 (2007).