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SUMMARY:GPCRs as Targets for Serial Crystallography
DTSTART;VALUE=DATE-TIME:20250923T080000Z
DTEND;VALUE=DATE-TIME:20250923T081500Z
DTSTAMP;VALUE=DATE-TIME:20260526T034235Z
UID:indico-contribution-1847@lindico453.srv.lu.se
DESCRIPTION:Speakers: Hannah Glover (leadXpro)\nUsing time-resolved serial
  crystallography to observe structural snapshots of protein dynamics at hi
 gh resolution is a method that is becoming gradually more commonplace. Adv
 ancements in method development for this technique have allowed a wider ra
 nge of proteins to be studied\; looking at processes spanning endogenous p
 hotoresponses\, enzyme kinetics and ligand binding. G protein-coupled rece
 ptors represent a pharmacologically relevant superfamily of proteins that 
 are interesting targets for study with time-resolved serial crystallograph
 y. Data from time-resolved serial crystallography has the potential to enh
 ance the drug design process by revealing protein transitional states that
  can be either targeted or used to provide information about protein flexi
 bility. Our goal is to study the inherent dynamics of GPCRs critical for r
 eceptor function and to use this information to develop more targeted liga
 nds. Here\, we present the results of time-resolved serial crystallography
  experiments conducted at MaxIV and the SLS on the human A2a receptor. Thr
 ough synthetic photoswitches\, based on the marketed drug istradefylline f
 or the treatment of Parkinson’s disease\, light is used as a trigger to 
 investigate the dynamics associated with ligand dissociation from the rece
 ptor orthosteric binding pocket. Our time-resolved data highlights key str
 uctural features involved in the transition upon ligand photoswitching. Th
 is includes the rearrangement of extracellular loops 2 and 3 that form a l
 id over the binding pocket\, which has been shown by molecular dynamic sim
 ulations\, crystal structures and kinetic analyses to be crucial for ligan
 d dissociation and long target resident time. Additionally\, lessons learn
 ed from this investigation\, in terms of experimental design and sample pr
 eparation\, can be applied to future projects using GPCRs as targets for s
 erial crystallography. Helping to lower the barrier of entry to time-resol
 ved serial crystallography and ultimately leading to more rationally desig
 ned drugs.\n\n\nCo-authors:\nTorben Saßmannshausen\, Quentin Bertrand\, M
 atilde Trabuco\, Chavdar Slavov\, Arianna Bacchin\, Fabio Andres\, Yasushi
  Kondo\, Robin Stipp\, Maximilian Wranik\, Georgii Khusainov\, Melissa Car
 rillo\, Demet Kekilli\, Jie Nan\, Ana Gonzalez\, Robert Cheng\, Werner Nei
 dhart\, Tobias Weinert\, Filip Leonarski\, Florian Dworkowski\, Michal Kep
 a\, Josef Wachtveitl\, Michael Hennig\, Joerg Standfuss\n\nhttps://lindico
 453.srv.lu.se/event/583/contributions/1847/
LOCATION:LINXS at The Loop
URL:https://lindico453.srv.lu.se/event/583/contributions/1847/
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