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SUMMARY:Enabling discovery by in-cell structural biology - Dr Julia Mahami
 d\, EMBL Heidelberg
DTSTART:20231115T103000Z
DTEND:20231115T113000Z
UID:TALK207250@talks.cam.ac.uk
CONTACT:Vaidehi Roy Chowdhury
DESCRIPTION:Most structural biology focuses on the structure and function 
 of individual macromolecular complexes\, but falls short of revealing how 
 they come together to give rise to cellular functions. Here\, cryo-electro
 n tomography (cryo-ET) provides a unique opportunity for obtaining structu
 ral information across a wide range of spatial scales - from small model o
 rganisms\, intact cells and 3D cultures frozen in their close-to-native st
 ate\, to individual macromolecular assemblies embedded in their native fun
 ctional environments. We develop and employ advanced sample preparation te
 chniques for in-cell cryo-ET\, including cryo-focused ion beam thinning gu
 ided by 3D correlative fluorescence microscopy. Preparations of such site-
 specific ‘electron-transparent windows’ in appropriate cellular model 
 systems enable assignment of molecular structures directly from three-dime
 nsional stills of intact cells and reveal their molecular sociology. Using
  the genome-reduced human pathogen Mycoplasma pneumoniae as a minimal cell
  model\, we further demonstrate the synergistic application of whole-cell 
 crosslinking mass spectrometry and cellular cryo-ET to determine an in-cel
 l integrative model of actively transcribing RNA polymerases coupled to a 
 translating ribosomes. Recent computational breakthroughs now allow resolv
 ing these molecular machines to residue-level directly inside the cell\, r
 eveal small molecule antibiotics bound to their active site in ribosomes w
 ithin the intact pathogen\, provide snapshots of their structural dynamics
  along reaction cycles\, and illuminate the existence and hint at function
 s of previously unknown macromolecular complexes. These cutting-edge metho
 dologies unlock an enormous potential for system-spanning discovery enable
 d by label-free in-cell structural biology.
LOCATION:Department of Chemistry\, Pfizer Lecture Theatre
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