TY - JOUR
T1 - Breaking free from the crystal lattice
T2 - Structural biology in solution to study protein degraders
AU - Haubrich, Kevin
AU - Spiteri, Valentina
AU - Farnaby, William
AU - Sobott, Frank
AU - Ciulli, Alessio
N1 - Funding Information:
Research in the Ciulli laboratory on targeted protein degraders and PROTACs receives or has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) as a Starting Grant (grant agreement No. ERC-2012-StG-311460 DrugE3CRLs to A.C.), and the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement no. 875510 (EUbOPEN project). The IMI2 Join Undertaking receives support from the European Union's Horizon 2020 research and innovation programme, EFPIA companies and Associated Partners: KTH, OICR, Diamond and McGill.
Copyright:
© 2023, The Authors
PY - 2023/4
Y1 - 2023/4
N2 - Structural biology offers a versatile arsenal of techniques and methods to investigate the structure and conformational dynamics of proteins and their assemblies. The growing field of targeted protein degradation centres on the premise of developing small molecules, termed degraders, to induce proximity between an E3 ligase and a protein of interest to be signalled for degradation. This new drug modality brings with it new opportunities and challenges to structural biologists. Here we discuss how several structural biology techniques, including nuclear magnetic resonance, cryo-electron microscopy, structural mass spectrometry and small angle scattering, have been explored to complement X-ray crystallography in studying degraders and their ternary complexes. Together the studies covered in this review make a case for the invaluable perspectives that integrative structural biology techniques in solution can bring to understanding ternary complexes and designing degraders.
AB - Structural biology offers a versatile arsenal of techniques and methods to investigate the structure and conformational dynamics of proteins and their assemblies. The growing field of targeted protein degradation centres on the premise of developing small molecules, termed degraders, to induce proximity between an E3 ligase and a protein of interest to be signalled for degradation. This new drug modality brings with it new opportunities and challenges to structural biologists. Here we discuss how several structural biology techniques, including nuclear magnetic resonance, cryo-electron microscopy, structural mass spectrometry and small angle scattering, have been explored to complement X-ray crystallography in studying degraders and their ternary complexes. Together the studies covered in this review make a case for the invaluable perspectives that integrative structural biology techniques in solution can bring to understanding ternary complexes and designing degraders.
UR - http://www.scopus.com/inward/record.url?scp=85148012148&partnerID=8YFLogxK
U2 - 10.1016/j.sbi.2023.102534
DO - 10.1016/j.sbi.2023.102534
M3 - Review article
C2 - 36804675
SN - 0959-440X
VL - 79
JO - Current Opinion in Structural Biology
JF - Current Opinion in Structural Biology
M1 - 102534
ER -