Research

Using cryo-electron microscopy, our lab has uncovered how Hsp90 and its partner chaperones orchestrate the maturation of client proteins essential for cell survival. We revealed the structure of Hsp90 in complex with the immunophilin FKBP51, showing for the first time how cochaperones recognize specific conformational states during the client maturation cycle. This discovery explains how cells coordinate the progression of client proteins through the chaperone machinery and opens new avenues for drug development targeting these protein-protein interactions.

Our recent structural studies of mitochondrial Hsp60 revealed an unexpected asymmetry in the chaperonin complex—the two rings of the barrel-shaped chaperonin adopt different conformations that coordinate substrate capture and folding. These findings demonstrate how chaperonins use asymmetric conformational states to prevent premature substrate release and ensure proper protein folding in the cellular environment.

In groundbreaking work on the p97/VCP AAA+ ATPase, we determined structures showing how the adaptor protein UBXD1 dramatically remodels p97, opening the hexameric ring through multi-domain tethered interactions. This mechanism represents a new paradigm for how adaptors control AAA+ machine assembly and reveals potential therapeutic targets for neurodegenerative diseases linked to p97 dysfunction.

Our laboratory pioneered the structural characterization of Hsp104, revealing its spiral architecture and the molecular basis for its remarkable ability to extract proteins from toxic aggregates. Through a series of cryo-EM structures capturing different nucleotide states, we discovered that Hsp104 uses a ratchet-like mechanism to translocate polypeptide chains through its central pore. By visualizing substrate-bound structures, we showed how pore loops grip and pull on unfolded regions of aggregated proteins, demonstrating for the first time the mechanical principles underlying protein disaggregation.

Our work extended to the related bacterial ClpAP protease, where we revealed how conformational plasticity couples ATP hydrolysis to both protein unfolding and proteolysis. The structures showed the AAA+ unfoldase ClpA positioned above the ClpP peptidase chamber, with substrate threading between them—a configuration that explains how cells coordinate mechanical unfolding with controlled degradation. These findings established fundamental principles for how AAA+ machines perform mechanical work on proteins.

We determined spiral architectures showing how substrate binding triggers coordinated conformational changes across the hexamer, creating a hand-over-hand mechanism for polypeptide translocation. This work provided the first direct visualization of how disaggregases grip misfolded proteins and pull them apart—insights that are now guiding efforts to engineer these machines for therapeutic applications against neurodegenerative diseases.

Our cryo-electron microscopy studies of nitric oxide synthase (NOS) revealed the first complete structural view of this critical signaling enzyme in its active state. We discovered that the holoenzyme undergoes large-scale conformational changes driven by calmodulin binding, which releases the FMN domain from the reductase and enables electron transfer to the catalytic heme domain. These structures explained a decades-old puzzle about how electrons flow through this complex multi-domain enzyme to enable nitric oxide production.

The flexible architecture we observed demonstrates how NOS exploits domain dynamics to coordinate the sequential electron transfers required for catalysis. This work established that NOS functions not as a rigid complex but as a conformationally dynamic machine where domain movements are integral to catalytic function. Understanding these dynamics is essential for understanding modulation of NO signaling in cardiovascular and neurological diseases.

Our laboratory has pioneered cryo-EM studies of disease-associated amyloid structures, providing molecular insights critical for developing diagnostics and understanding hallmarks of disease. We determined the structure of tau paired helical filaments in complex with PET imaging ligands, revealing that these small molecules bind through stacked interactions within the fibril core. This discovery explained the binding specificity of diagnostic imaging agents and provided a structural template for designing next-generation compounds with improved properties.

These structural studies bridge basic science and clinical application, showing how atomic-resolution insights into pathological protein assemblies can directly inform medical imaging and drug discovery. Our work demonstrates that disease-associated protein aggregates adopt specific three-dimensional structures—not random tangles—making them targetable with structure-based approaches.