Teresa Carlomagno
School of Biosciences, College of Life and Environmental Sciences and Department of Cancer and Genomic Sciences, College of Medicine and Health, University of Birmingham, UK
An integrative structural biology approach to understand functional mechanisms in biological complexes
After >60 years of structural biology, the complexity of both the molecules we study and the questions we pose has increased enormously. Nowadays, we aim to achieve complete spatial/temporal characterization of large molecular complexes during their function, as well as understand the functional mechanisms of disorder and the role of conformational dynamics. In this context, the direction of travel for structural biology is towards integrative methods, where complementarities across cutting-edge technologies are leveraged to address more challenging systems and to understand functional mechanisms in greater depth.
Magnetic resonance makes vital contributions across physical, biological and medical fields, due to its unique ability to study molecules in both the spatial and temporal dimensions, reveal minorly populated conformations and cope with structural disorder. Furthermore, methyl TROSY and 15N,13C-direct-detection experiments allow molecular species as large as 1 MDa to be interrogated by solution NMR.
In our laboratory, we use and develop integrative structural biology approaches that employ NMR together with complementary methods to understand the functional mechanism of high-molecular-weight complexes with enzymatic activity. Integrative structural biology in solution is particularly relevant for enzymes that contain disordered or flexible parts and for transiently forming complexes, all cases where X-ray crystallography or electron microscopy fail.
I will demonstrate the approach on the example of two large biomolecular complexes. The first complex contains large, disordered regions (1), while the second complex has a short life-time (2) as well as intra and interdomain dynamics.
Selected references
1. N. Danilenko, L. Lercher, F. Gabel, J. Kirkpatrick, T. Carlomagno. Histone chaperone exploits intrinsic disorder to switch acetylation specificity Nature Communications (2019) 10: 3435
2. M.N. Karanth, J.P. Kirkpatrick, J. Krausze, S. Schmelz, A. Scrima, T. Carlomagno. The specificity of intermodular recognition in a prototypical non-ribosomal peptide synthetase depends on an adaptor domain Science Advances (2024) 10: eadm9404