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@ARTICLE{Chen:448363,
      author       = {Chen, Po-chia and Masiewicz, Pawel and Perez, Kathryn and
                      Hennig, Janosch},
      title        = {{S}tructure-based screening of binding affinities via
                      small-angle {X}-ray scattering},
      journal      = {IUCrJ},
      volume       = {7},
      number       = {4},
      issn         = {2052-2525},
      address      = {Chester},
      reportid     = {PUBDB-2020-03391},
      pages        = {644 - 655},
      year         = {2020},
      abstract     = {Protein–protein and protein–ligand interactions often
                      involve conformational changes or structural rearrangements
                      that can be quantified by solution small-angle X-ray
                      scattering (SAXS). These scattering intensity measurements
                      reveal structural details of the bound complex, the number
                      of species involved and, additionally, the strength of
                      interactions if carried out as a titration. Although a core
                      part of structural biology workflows, SAXS-based titrations
                      are not commonly used in drug discovery contexts. This is
                      because prior knowledge of expected sample requirements,
                      throughput and prediction accuracy is needed to develop
                      reliable ligand screens. This study presents the use of the
                      histidine-binding protein (26 kDa) and other periplasmic
                      binding proteins to benchmark ligand screen performance.
                      Sample concentrations and exposure times were varied across
                      multiple screening trials at four beamlines to investigate
                      the accuracy and precision of affinity prediction. The
                      volatility ratio between titrated scattering curves and a
                      common apo reference is found to most reliably capture the
                      extent of structural and population changes. This obviates
                      the need to explicitly model scattering intensities of bound
                      complexes, which can be strongly ligand-dependent. Where the
                      dissociation constant is within 10$^2$ of the protein
                      concentration and the total exposure times exceed 20 s,
                      the titration protocol presented at 0.5 mg ml$^{−1}$
                      yields affinities comparable to isothermal titration
                      calorimetry measurements. Estimated throughput ranges
                      between 20 and 100 ligand titrations per day at current
                      synchrotron beamlines, with the limiting step imposed by
                      sample handling and cleaning procedures.},
      cin          = {EMBL-User},
      ddc          = {530},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (POF3-622)},
      pid          = {G:(DE-HGF)POF3-6G3},
      experiment   = {EXP:(DE-H253)P-P12-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32695411},
      UT           = {WOS:000548507200007},
      doi          = {10.1107/S2052252520004169},
      url          = {https://bib-pubdb1.desy.de/record/448363},
}