title: MOTOR: model assisted software for NMR structure determination.
abstract: Eukaryotic proteins with important biological function can be partially unstructured, conformational flexible, or heterogenic. Crystallization trials often fail for such proteins. In NMR spectroscopy, parts of the polypeptide chain undergoing dynamics in unfavorable time regimes cannot be observed. De novo NMR structure determination is seriously hampered when missing signals lead to an incomplete chemical shift assignment resulting in an information content of the NOE data insufficient to determine the structure ab initio. We developed a new protein structure determination strategy for such cases based on a novel NOE assignment strategy utilizing a number of model structures but no explicit reference structure as it is used for bootstrapping like algorithms. The software distinguishes in detail between consistent and mutually exclusive pairs of possible NOE assignments on the basis of different precision levels of measured chemical shifts searching for a set of maximum number of consistent NOE assignments in agreement with 3D space. Validation of the method using the structure of the low molecular-weight-protein tyrosine phosphatase A (MptpA) showed robust results utilizing protein structures with 30-45% sequence identity and 70% of the chemical shift assignments. About 60% of the resonance assignments are sufficient to identify those structural models with highest conformational similarity to the real structure. The software was benchmarked by de novo solution structures of fibroblast growth factor 21 (FGF21) and the extracellular fibroblast growth factor receptor domain FGFR4 D2, which both failed in crystallization trials and in classical NMR structure determination.
authors.affiliation: Johann Wolfgang Goethe-University Frankfurt, Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Max-von-Laue-Str. 7, 60438, Frankfurt am Main, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schieborr
authors.forename: Sridhar
authors.initials: S
authors.lastname: Sreeramulu
authors.forename: Bettina
authors.initials: B
authors.lastname: Elshorst
authors.forename: Marcus
authors.initials: M
authors.lastname: Maurer
authors.forename: Krishna
authors.initials: K
authors.lastname: Saxena
authors.forename: Tanja
authors.initials: T
authors.lastname: Stehle
authors.forename: Denis
authors.initials: D
authors.lastname: Kudlinzki
authors.forename: Santosh Lakshmi
authors.initials: SL
authors.lastname: Gande
authors.forename: Harald
authors.initials: H
authors.lastname: Schwalbe
mesh_terms: D000465:Algorithms; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D011506:Proteins / Q000737:chemistry*; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry; D012984:Software
chemical_list: D011506:Proteins; D017468:Receptors, Fibroblast Growth Factor
keywords: NOE; algorithm; assignment; fibroblast growth factor; fibroblast growth factor receptor; protein; software; sparse data