title: Conformational Rigidity within Plasticity Promotes Differential Target Recognition of Nerve Growth Factor.
abstract: Nerve Growth Factor (NGF), the prototype of the neurotrophin family, is essential for maintenance and growth of different neuronal populations. The X-ray crystal structure of NGF has been known since the early '90s and shows a β-sandwich fold with extensive loops that are involved in the interaction with its binding partners. Understanding the dynamical properties of these loops is thus important for molecular recognition. We present here a combined solution NMR/molecular dynamics study which addresses the question of whether and how much the long loops of NGF are flexible and describes the N-terminal intrinsic conformational tendency of the unbound NGF molecule. NMR titration experiments allowed identification of a previously undetected epitope of the anti-NGF antagonist antibody αD11 which will be of crucial importance for future drug lead discovery. The present study thus recapitulates all the available structural information and unveils the conformational versatility of the relatively rigid NGF loops upon functional ligand binding.
authors.affiliation: Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research, Rita Levi-Montalcini FoundationRome, Italy; Scuola Normale SuperiorePisa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Paoletti
authors.affiliation: The Francis Crick Institute London, UK.
authors.forename: Cesira
authors.initials: C
authors.lastname: de Chiara
authors.affiliation: Medical Research Council (MRC) Biomedical NMR Centre, The Francis Crick Institute London, UK.
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche (CNR), Sede Secondaria di Basovizza Trieste, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Covaceuszach
authors.affiliation: Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research, Rita Levi-Montalcini FoundationRome, Italy; Scuola Normale SuperiorePisa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Malerba
authors.affiliation: Maurice Wohl Institute, Department of Basic and Clinical Neuroscience, King's College London London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Yan
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche (CNR), Sede Secondaria di Basovizza Trieste, Italy.
authors.forename: Doriano
authors.initials: D
authors.lastname: Lamba
authors.affiliation: Neurotrophic Factors and Neurodegenerative Diseases Unit, European Brain Research, Rita Levi-Montalcini FoundationRome, Italy; Scuola Normale SuperiorePisa, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
authors.affiliation: Maurice Wohl Institute, Department of Basic and Clinical Neuroscience, King's College LondonLondon, UK; Molecular Medicine Department, University of PaviaPavia, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
keywords: NGF; NMR; antibody recognition; neurodegeneration; neurotrophins; structure