BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//CERN//INDICO//EN
BEGIN:VEVENT
SUMMARY:Using neutrons to elucidate the molecular details of enzyme isofor
 m selectivity by small molecule inhibitors.
DTSTART;VALUE=DATE-TIME:20181120T000000Z
DTEND;VALUE=DATE-TIME:20181120T003000Z
DTSTAMP;VALUE=DATE-TIME:20260416T051113Z
UID:indico-contribution-2293@events01.synchrotron.org.au
DESCRIPTION:Speakers: Zoë Fisher (European Spallation Source ERIC)\nHuman
  carbonic anhydrase IX (CA IX) expression is activated by hypoxic conditio
 n in aggressive\, metastatic tumors. Cancer patietns positive for CA IX ha
 ve generally a poor prognosis. CA IX has emerged as an important cancer ta
 rget\, but efforts to develop isoform selective inhibitors are complicated
  by the presence of 14 other CA isoforms that share high sequence and stru
 ctural similarity. This leads to off-target inhibitor binding and side eff
 ects. Recent studies showed that saccharin (SAC) already shows some isofor
 m discrimination\, and that conjugating SAC to a glucose molecule (Sacchar
 in-Glucose Conjugate\, SGC) further improves the Ki against CA IX by 2-fol
 d. \nLigand binding to proteins are mediated through numerous interactions
 \, including: H-bonding directly and/or through intervening waters\, elect
 rostatic interactions with charged or polar amino acid side chains\, metal
  coordination\, energetic changes through water displacement\, aromatic ri
 ng stacking\, or other hydrophobic interactions. As neutrons scatter stron
 gly from atomic nuclei of light atoms 1H (Hydrogen)\, and its isotope 2H (
 Deuterium)\, it is possible to use neutron protein crystallography (NPX) t
 o “see” the light atoms and any interactions they are involved with. (
 e.g. H-bonds). \nWe used joint X-ray and neutron crystallography methods t
 o determine the crystal structures of a CA IX mimic alone and in complex w
 ith SAC and SGC\, respectively. Our analyses reveal the molecular details 
 of solvent displacement upon ligand binding\, the H-bonding between the li
 gands and the proteins\, involvement of water-mediated H-bonds\, and the r
 emodeling of H-bonds to accommodate ligand binding. The structures and ana
 lysis also provide an explanation for the observed CA isoform selectivity 
 of the ligand under study.\n\nhttps://events01.synchrotron.org.au/event/84
 /contributions/2293/
LOCATION:AINSE Conference Centre New Illawarra Road Lucas Heights NSW 2234
  Australia
URL:https://events01.synchrotron.org.au/event/84/contributions/2293/
END:VEVENT
END:VCALENDAR