Characterization of the structure, dynamics and allosteric pathways of human NPP1 in its free form and substrate-bound complex from molecular modeling.

Abstract:

:The ectonucleotide phosphodiesterase/pyrophosphatase-1 (NPP1) is a type II transmembrane glycoprotein that regulates extracellular inorganic purine nucleotide and inorganic diphosphate levels through the hydrolysis of ATP into AMP and diphosphate. NPP1 is a promising drug target as it plays a role in several disorders. In the present work, we report the 3D structure modeling and extensive molecular dynamics simulations of NPP1-h, both in its free and ATP-bound forms. We identified the key residues involved in the binding of the ATP and the binding modes. The simulations suggest that NPP1-h is a rigid enzyme except for specific residues or segments, with the most mobile residues located in the unstructure "lasso loop" (LSO) domain. The binding of ATP significantly affected the dynamics of NPP1-h, with a rigidification of the phosphodiesterase (PDE) catalytic domain and an increase in mobility for the residues of the Nuclease-like (NUC) and the LSO domains. A dynamical network analysis identified that the most prevalent edges of the networks were located between the PDE and the NUC domains. In presence of ATP the networks became scattered through the PDE domain while the networks converged into a specific path that stretched from the PDE-NUC interdomain up to the middle of the LSO loop throughout the NUC domain. We suggest that these sections of the dynamical network may host potential allosteric inhibition sites. These results provide an improved understanding of the structure and dynamics of NPP1-h and will contribute to the rational design of NPP1-h inhibitors.

journal_name

Mol Biosyst

journal_title

Molecular bioSystems

authors

Barbeau X,Mathieu P,Paquin JF,Lagüe P

doi

10.1039/c7mb00095b

subject

Has Abstract

pub_date

2017-05-30 00:00:00

pages

1058-1069

issue

6

eissn

1742-206X

issn

1742-2051

journal_volume

13

pub_type

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