|Complete all-atom model of HIV-1 capsid (Nature 497:643, 2013, featured on Nature Cover).|
|Bacterial chemosensory arrays (Elife 4:e08419, 2015)|
|Direct visualization of HIV-1 infection using correlative microscopy (Structure 19:1573, 2011)|
Professor of Structural Biology and WELLCOME TRUST INVESTIGATOR
Structural Biology of Human Pathogens
Our research is aimed at an integrated, atomistic understanding of molecular mechanisms of virus and bacteria infections by developing and combining novel technologies for high-resolution cryoEM and cryo-electron tomography with complementary computational and biophysical/biochemical methods. Current research efforts in our lab are directed to:
HIV-1 capsid assembly, maturation, and interactions with host cell factors
Retroviruses, such as human immunodeficiency virus 1 (HIV-1), contain mature conical capsids that enclose the viral RNA genome, enzymes and accessory proteins. The assembly and stability of the viral capsid are critical to the viral replication life cycle. Structures of the building blocks of the capsid assembly were determined to atomic level, the mechanisms of capsid assembly and disassembly during a productive infection, however, remain unclear. Such information is essential for the development of therapeutic drugs that target viral capsid. More importantly, the surface of HIV-1 capsid serves a primary interaction interface between the virus and the host cell. Many host defense proteins have been identified to interact with the viral capsid and block HIV-1 infection. Yet, very little is known about their precise recognition and interactions, and thus mechanisms of inhibition. We are developing cutting-edge cryoEM technologies that bring unprecedented resolution and enable in situ structures of HIV-1 and in complex with host proteins, such as CypA, TRIM5α, TRIMCyp, CPSF6 and MxB, to decipher their underlining functional roles
Bacterial chemotaxis sensory arrays
Bacteria use chemotaxis signaling pathways to monitor their environment and respond appropriately to change, which is crucial for colonization and infection for bacterial pathogens. The essential core signaling unit comprises transmembrane receptors, a histidine kinase CheA, and a coupling protein CheW. Remarkably, bacteria accomplish the extraordinary gain and cooperativity in chemotaxis signaling by arranging a few hundred core signaling units into higher order arrays localized at the cell pole. We aim to determine the precise molecular mechanisms of chemotaxis cooperative signaling using high-resolution cryoEM and cryoET in combination with site-directed mutagenesis and computational modeling. Our long-term goal is to develop plausible molecular models, at atomic resolution, for the entire signaling pathway by assembling structural “snapshots” of the signaling states.
CryoEM technology development
Driven by biological questions and inspired by the bottlenecks we have to overcome, we devote significant efforts to the advancement of novel cryoEM methods and technologies. We are working on a wide spectrum of technical advances that will be essential to realize the promise of imaging cells and tissues at molecular resolutions, including correlative microscopy, cryo-FIB/SEM and high resolution sub-tomogram classification and averaging.
Wellcome Trust Investigator Award: Molecular mechanisms of HIV-1 restriction by capsid-sensing host cell proteins
BBSRC project grant: Assembly and Dynamics of Bacterial Chemosensory Signaling Arrays
NIH/NIAID: University of Pittsburgh Center for HIV Protein Interactions (PCHPI)-CryoEM Core
ERC AdG grant: Molecular choreography of bacterial chemotaxis signalling
Correlative Multi-scale Cryo-imaging Unveils SARS-CoV-2 Assembly and Egress.
Zhang P. et al, (2021), Res Sq
Intrinsic curvature of the HIV-1 CA hexamer underlies capsid topology and interaction with cyclophilin A.
Ni T. et al, (2020), Nat Struct Mol Biol
Structure of native HIV-1 cores and their interactions with IP6 and CypA.
Ni T. et al, (2021), Sci Adv, 7
Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics
Zhao G. et al, (2013), Nature, 497, 643 - 646
emClarity: software for high-resolution cryo-electron tomography and subtomogram averaging
Himes BA. and Zhang P., (2018), Nature Methods, 15, 955 - 961
High-resolution in situ structure determination by cryo-electron tomography and subtomogram averaging using emClarity.
Ni T. et al, (2022), Nature protocols
Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site
Liu C. et al, (2016), Nature Communications, 7
Assembly intermediates of orthoreovirus captured in the cell.
Sutton G. et al, (2020), Nature communications, 11
Structure and dynamics of the E. coli chemotaxis core signaling complex by cryo-electron tomography and molecular simulations
Cassidy CK. et al, (2020), Communications Biology, 3
CryoEM structure of the super-constricted two-start dynamin 1 filament
Liu J. et al, (2021), Nature Communications, 12