Homology-based Structural Modeling of TGFBR2

Because no experimental structure of TGFBR2 exists, we queried to the PDB (Berman et al. 2000 (link)) using T-Coffee (Di Tommaso et al. 2011 (link)) and generated a homology-based model against the best available template using MODELLER (Sali and Blundell 1993 (link)) version 9.15. The template of adenine-bound ACVR2B, 2QLU (Han et al. 2007 (link)) exhibited 46% sequence identity for the modeled region. We generated 20 models and selected the model with the lowest DOPE (discrete optimized protein energy) score (Shen and Sali 2006 (link)) for further analyses. Model quality was assessed using PROCHECK (Laskowski et al. 1996 (link)), QMEAN (Benkert et al. 2009 (link)) and VADAR version 1.8 (Willard et al. 2003 (link)). Pathogenic and likely pathogenic missense variants were extracted from ClinVar (Landrum et al. 2014 (link)) and mapped to our TGFBR2 model. In silico mutagenesis was performed using Discovery Studio (Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2017). Changes in folding energy upon mutation (ΔΔG_fold) were computed using FoldX version 4 (Schymkowitz et al. 2005 (link); Van Durme et al. 2011 (link)).

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Cousin M.A., Zimmermann M.T., Mathison A.J., Blackburn P.R., Boczek N.J., Oliver G.R., Lomberk G.A., Urrutia R.A., Deyle D.R, & Klee E.W. (2017). Functional validation reveals the novel missense V419L variant in TGFBR2 associated with Loeys–Dietz syndrome (LDS) impairs canonical TGF-β signaling. Cold Spring Harbor Molecular Case Studies, 3(4), a001727.

Publication 2017

Discovery Studio

Acvr2b Adenine Coffee Missense variants Mutagenesis Mutation Pathogenic Protein Tgfbr2

Corresponding Organization :

Other organizations : Mayo Clinic in Florida, Mayo Clinic

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Variable analysis

independent variables

Adenine-bound ACVR2B template (2QLU) with 46% sequence identity for the modeled region

dependent variables

Selection of the model with the lowest DOPE (discrete optimized protein energy) score
Assessment of model quality using PROCHECK, QMEAN, and VADAR
Mapping of pathogenic and likely pathogenic missense variants from ClinVar to the TGFBR2 model
Computation of changes in folding energy upon mutation (ΔΔG_fold) using FoldX version 4

control variables

No experimental structure of TGFBR2 exists
Use of T-Coffee for generating the homology-based model
Use of MODELLER version 9.15 for generating 20 models and selecting the one with the lowest DOPE score

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