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J Chem Inf Model. 2014 Jul 28;54(7):2051-67. doi: 10.1021/ci500101n. Epub 2014 Jun 27.

Dynamic structure of NGF and proNGF complexed with p75NTR: pro-peptide effect.

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REQUIMTE Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto , Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.


Crystallographic structures of NGF/p75NTR and proNGF/p75NTR were previously obtained in 2:1 and 2:2 stoichiometries, respectively. However, evidence shows that both stoichiometries can occur for mature neurotrophins and pro-neurotrophins. We used Molecular Dynamics (MD) simulations to examine the energetic and structural characteristics of these two complete systems as well as the uncomplexed forms of NGF and understand how these could translate in a new view of different biological outcomes. Here, we show that one chain at the 2:2 proNGF complex seems to be preferentially lost creating a 2:1 structure able to interact with sortilin. We also demonstrated that the structure of the neurotrophin dimers is not pre-established and suffers large structural modifications upon p75NTR binding. Moreover, our data suggests an elegant explanation for the dual role of NGF in neuronal cell death and survival, where different stoichiometries induce conformational changes that might be the basis for the different biological outcomes observed with the mature and proforms of neurotrophins.

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