Small Angle X-ray Scattering, Molecular Modeling, and Chemometric Studies from a Thrombin-Like (Lmr-47) Enzyme of Lachesis m. rhombeata Venom

Snakebite envenomation is considered a neglected tropical disease, and SVTLEs critical elements are involved in serious coagulopathies that occur on envenoming. Although some enzymes of this group have been structurally investigated, it is essential to characterize other proteins to better understan...

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Published in:	Molecules (Basel, Switzerland) Vol. 26; no. 13; p. 3930
Main Authors:	De-Simone, Salvatore Giovanni, Lechuga, Guilherme Curty, Napoleão-Pêgo, Paloma, Gomes, Larissa Rodrigues, Provance, Jr, David William, Nirello, Vinícius Dias, Sodero, Ana Carolina Rennó, Guedes, Herbert Leonel de Mattos
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 28-06-2021 MDPI
Subjects:	Animals Crotalid Venoms - enzymology Crotalinae Elongated structure Enzymes Fluorescence Gas detectors guanidine inhibitors Homology Inhibitors Lachelis m. rhombeata Modelling Molecular docking Molecular Docking Simulation Molecular modelling Molecular structure Principal components analysis protein shape Protein structure Proteins Reptilian Proteins - chemistry Scattering, Small Angle Secondary structure Serine serine protease Serine proteinase Snake bites solution structure SVTLE Thrombin Thrombin - chemistry Variables Venom X-Ray Diffraction X-ray scattering SVTLE solution structure Lachelis m. rhombeata guanidine inhibitors protein shape serine protease amidine inhibitors
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Summary:	Snakebite envenomation is considered a neglected tropical disease, and SVTLEs critical elements are involved in serious coagulopathies that occur on envenoming. Although some enzymes of this group have been structurally investigated, it is essential to characterize other proteins to better understand their unique properties such as the 47 kDa (Lmr-47) venom serine protease. The structure of Lmr-47 was studied in solution, using SAXS, DLS, CD, and in silico by homology modeling. Molecular docking experiments simulated 21 competitive inhibitors. At pH 8.0, Lmr-47 has an Rg of 34.5 ± 0.6 Å, Dmax of 130 Å, and SR of 50 Å, according to DLS data. Kratky plot analysis indicates a rigid shape at pH 8.0. Conversely, the pH variation does not change the center of mass's intrinsic fluorescence, possibly indicating the absence of fluorescent amino acids in the regions affected by pH variation. CD experiments show a substantially random coiled secondary structure not affected by pH. The low-resolution model of Lmr-47 presented a prolate elongated shape at pH 8.0. Using the 3D structure obtained by molecular modeling, docking experiments identified five good and three suitable competitive inhibitors. Together, our work provided insights into the structure of the Lmr-47 and identified inhibitors that may enhance our understanding of thrombin-like family proteins.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-3049 1420-3049
DOI:	10.3390/molecules26133930