Nikola P. Pavletich

Solved the crystal structure of the mTOR kinase itself, revealing the FRB "gatekeeper" that guards its active site

BS in Chemistry, Caltech (1988) · PhD, Johns Hopkins University School of Medicine (1991) · postdoc, MIT (Carl Pabo lab) · faculty, Memorial Sloan Kettering Cancer Center (since 1993) · HHMI Investigator (1997–2022) · Chair, Structural Biology Program · now Stephen and Barbara Friedman Chair, Sloan Kettering Institute

Pavletich Lab, Memorial Sloan Kettering Cancer Center ↗

In 2013, Pavletich's lab solved the first crystal structure of the mTOR kinase domain itself — a feat that had eluded structural biologists for years because mTOR is a huge, flexible, membrane-associated enzyme. The structure showed why mTOR's active site is so hard for drugs and substrates to reach: it sits in a deep recess, and the FRB domain acts as a lid or 'gatekeeper' controlling access, explaining at the atomic level exactly how the FKBP12–rapamycin complex jams the site shut, and why activating cancer mutations cluster around it. In 2017, his group followed up with structures of the full mTORC1 complex bound to its regulators, showing mechanistically how the small GTPase RHEB docks onto mTOR and allosterically realigns its catalytic residues to turn the kinase on, while the inhibitory subunit PRAS40 works by occluding the substrate-binding surface.

The mTOR work came after two decades in which Pavletich's lab built a track record of solving landmark, previously 'unsolvable' cancer-related protein structures by X-ray crystallography: the p53 tumour-suppressor core domain bound to DNA (1994); the MDM2–p53 transactivation-domain complex, which defined the druggable pocket later exploited by MDM2-inhibitor cancer drugs such as the Nutlins (1996); the p27Kip1–cyclin A–Cdk2 complex, showing how p27 both rearranges and physically plugs the kinase's ATP cleft to halt the cell cycle (1996); and the VHL–ElonginC–ElonginB complex, revealing the tumorigenic hot-spot on the von Hippel–Lindau protein (1999).

Pavletich trained in chemistry at Caltech, earned his PhD at Johns Hopkins, and did postdoctoral work with Carl Pabo at MIT before joining Memorial Sloan Kettering Cancer Center's faculty in 1993, becoming an HHMI Investigator in 1997 and Chair of the Structural Biology Program in 2003. He was elected to the National Academy of Sciences in 2012. His lab's current focus has extended from mTOR to the structural biology of DNA-damage-response machinery, including the ATR and ATM checkpoint kinases and the Fanconi anemia pathway.

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