Molecular dynamics simulations reveal structural insights into inhibitor binding modes and functionality in human group IIA phospholipase A2

Kim, Ryung Rae, Malde, Alpeshkumar K., Nematollahi, Alireza, Scott, Kieran F. and Church, W. Bret (2017) Molecular dynamics simulations reveal structural insights into inhibitor binding modes and functionality in human group IIA phospholipase A2. Proteins: Structure, Function, and Bioinformatics, 85 5: 827-842. doi:10.1002/prot.25235


Author Kim, Ryung Rae
Malde, Alpeshkumar K.
Nematollahi, Alireza
Scott, Kieran F.
Church, W. Bret
Title Molecular dynamics simulations reveal structural insights into inhibitor binding modes and functionality in human group IIA phospholipase A2
Formatted title
Molecular dynamics simulations reveal structural insights into inhibitor binding modes and functionality in human group IIA phospholipase A2
Journal name Proteins: Structure, Function, and Bioinformatics   Check publisher's open access policy
ISSN 1097-0134
0887-3585
Publication date 2017-01-05
Sub-type Article (original research)
DOI 10.1002/prot.25235
Open Access Status Not Open Access
Volume 85
Issue 5
Start page 827
End page 842
Total pages 44
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Formatted abstract
Human group IIA phospholipase A2 (hGIIA) promotes inflammation in immune-mediated pathologies by regulating the arachidonic acid pathway through both catalysis-dependent and -independent mechanisms. The hGIIA crystal structure, both alone and inhibitor-bound, together with structures of closely related snake-venom-derived secreted phospholipase enzymes has been well described. However, differentiation of biological and non-biological contacts and the relevance of structures determined from snake venom enzymes to human enzymes are not clear. We employed molecular dynamics (MD) and docking approaches to understand the binding of inhibitors that selectively or non-selectively block the catalysis-independent mechanism of hGIIA. Our results indicate that hGIIA behaves as a monomer in the solution environment rather than a dimer arrangement that is in the asymmetric unit of some crystal structures. The binding mode of a non-selective inhibitor, KH064, was validated by a combination of the experimental electron density and MD simulations. The binding mode of the selective pentapeptide inhibitor FLSYK to hGIIA was stipulated to be different to that of the snake venom phospholipases A2 of Daboia russelli pulchella (svPLA2). Our data suggest the application of molecular dynamics approaches to crystal structure data is beneficial in evaluating the robustness of conclusions drawn based on crystal structure data alone.
Keyword FLSYK inhibitor
Group IIA phospholipase A2
Binding site
Docking
Molecular dynamics
Protein-protein interaction
Vimentin
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 13 Jan 2017, 21:00:59 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences