Nicholas A. Larsen

Research Summary

I graduated from Carleton College majoring in chemistry and physics, and earned a PhD from the Scripps Research Institute with Ian Wilson, in structural biology. In my thesis, we characterized a cocaine degrading enzyme, now in preclinical trials as a biologic antidote for toxic cocaine overdose (1, 2). Subsequently, I moved to Harvard to work with Stephen Harrison to study the kinetochore / mitotic spindle checkpoint (3, 4, 5), and to pursue eclectic interests in collaboration with Christopher Walsh and Graham Walker – including antibiotic, enterobactin (6), and vitamin B12 biosynthesis (7). I have discovered firsthand that while crystallography is an incredibly powerful technique for studying enzyme mechanism and function, static snapshots reveal little about the intricately choreographed interactions of proteins in complex systems; orthogonal experimental approaches are required to fully understand their function. Therefore, I crossed the quad to Marc Kirschner’s Laboratory in 2006.

The goal is to integrate the inherently reductionistic approach of the crystallographer with a broader systems approach used in Marc’s laboratory to understand cellular checkpoints and circuits. My current efforts are directed towards identifying new substrates of the Anaphase Promoting Complex (APC) and purifying APC for structural and biochemical studies.

References

(1) Larsen NA, Turner JM, Stevens J, Rosser SJ, Basran A, Lerner RA, Bruce NC, Wilson IA. (2002) Crystal structure of a bacterial cocaine esterase. Nat Struct Mol Biol. 9, 17-21.

(2) Cooper ZD, Narasimhan D, Sunahara RK, Mierzejewski P, Jutkiewicz EM, Larsen NA, Wilson IA, Landry DW, Woods JH. (2006) Rapid and robust protection against cocaine-induced lethality in rats by a bacterial esterase. Mol Pharmacol. 70, 1885-1891.

(3) Larsen NA, Al-Bassam J, Wei RR, Harrison SC. (2007) Structural analysis of Bub3 interactions in the mitotic spindle checkpoint. PNAS 104, 1201-1206.

(4) Al-Bassam J, Larsen NA, Hyman AA, Harrison SC. (2007) Crystal structure of a TOG domain: conserved features of XMAP215/Dis1-family TOG domains and implications for Tubulin binding. Structure 15, 355-362.

(5) Wei RR, Schnell JR, Larsen NA, Sorger PK, Chou J, Harrison SC. (2006) Structure of a central component of the yeast kinetochore: the Spc24p/Spc25p globular domain. Structure 14, 1003-1009.

(6) Larsen NA, Lin H, Wei RR, Fischbach MA, Walsh CT. (2006) Structural characterization of enterobactin hydrolase IroE. Biochemistry 45, 10184-10190.

(7) Taga ME*, Larsen NA*, Howard-Jones AR, Walsh CT, Walker GC. (2007) BluB cannibalizes flavin to form the lower ligand of vitamin B12. Nature 446, 449-453.