Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme

Mohd Imran Khan, Gururao Hariprasad Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, IndiaCorrespondence: Gururao Hariprasad Tel +91-11-26594240Fax +91-11-26588663Email g.hariprasad@rediffmail.comPurpose: To investigate the structural features of wild and mutant f...

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Autores principales:	Khan MI, Hariprasad G
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	platelet activating factor acetyl hydrolase structure molecular modelling mutations v279f q281r clinical phenotype coronary artery disease Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/154d4218684746ba8238f04ee62d49b2
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spelling	oai:doaj.org-article:154d4218684746ba8238f04ee62d49b22021-12-02T12:03:04ZStructural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme1178-7031https://doaj.org/article/154d4218684746ba8238f04ee62d49b22020-12-01T00:00:00Zhttps://www.dovepress.com/structural-modeling-of-wild-and-mutant-forms-of-human-plasma-platelet--peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Mohd Imran Khan, Gururao Hariprasad Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, IndiaCorrespondence: Gururao Hariprasad Tel +91-11-26594240Fax +91-11-26588663Email g.hariprasad@rediffmail.comPurpose: To investigate the structural features of wild and mutant forms of the pPAF-AH enzyme that are responsible for coronary artery disease.Methods: Mutant variants of human pPAF-AH having either V279F, Q281R, or both were modelled and evaluated for stereo chemical and structural correctness. The 3D coordinates of substrate PAF were retrieved from the PubChem database was solvated and minimized on Discovery Studio, and docked to the wild and mutant enzyme models. The top docked pose complex was refined by MD simulation.Results: pPAF-AH model comprises of 420 amino acids in a α/β-hydrolase fold that contains a substrate-binding hydrophobic channel with an active site pocket having a catalytic triad of Ser273, Asp296 and His351. Mutations at positions 279 and 281 are opposite one another on the middle of 12 residues long H5 helix that forms the hydrophobic core of the enzyme. V279F causes a tilt on the axis of the mutation bearing helix to avoid steric clashes with the hydrophobic residues on the β-sheets adjacent to it, inducing subtle conformational changes on the H5-β 8 loop, β 8 sheet, and the loop bearing Asp296. A cascade of conformational changes induces a change in the orientation of His351 resulting in loss of hydrogen bonded interaction with catalytic Ser273. Q281R causes a shortening of H5 and β 8, which induces conformational changes of the loops bearing Ser273 and Asp296, respectively. Simultaneous conformational changes of secondary structural elements result in the flipping of His351 causing a break in the catalytic triad. Also, there is a compromise in the substrate-binding area and volume in the mutants resulting in loss of binding to its substrate.Conclusion: Mutant enzymes show changes at the site of the mutation, secondary motif conformations and global structural conformations that adversely affect the active site, decrease substrate channel volume and decrease stability, thereby affecting enzymatic function.Keywords: platelet activating factor acetyl hydrolase, structure, molecular modelling, mutations, V279F, Q281R, clinical phenotype, coronary artery diseaseKhan MIHariprasad GDove Medical Pressarticleplatelet activating factor acetyl hydrolasestructuremolecular modellingmutationsv279fq281rclinical phenotypecoronary artery diseasePathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 13, Pp 1125-1139 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	platelet activating factor acetyl hydrolase structure molecular modelling mutations v279f q281r clinical phenotype coronary artery disease Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	platelet activating factor acetyl hydrolase structure molecular modelling mutations v279f q281r clinical phenotype coronary artery disease Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Khan MI Hariprasad G Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme
description	Mohd Imran Khan, Gururao Hariprasad Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, IndiaCorrespondence: Gururao Hariprasad Tel +91-11-26594240Fax +91-11-26588663Email g.hariprasad@rediffmail.comPurpose: To investigate the structural features of wild and mutant forms of the pPAF-AH enzyme that are responsible for coronary artery disease.Methods: Mutant variants of human pPAF-AH having either V279F, Q281R, or both were modelled and evaluated for stereo chemical and structural correctness. The 3D coordinates of substrate PAF were retrieved from the PubChem database was solvated and minimized on Discovery Studio, and docked to the wild and mutant enzyme models. The top docked pose complex was refined by MD simulation.Results: pPAF-AH model comprises of 420 amino acids in a α/β-hydrolase fold that contains a substrate-binding hydrophobic channel with an active site pocket having a catalytic triad of Ser273, Asp296 and His351. Mutations at positions 279 and 281 are opposite one another on the middle of 12 residues long H5 helix that forms the hydrophobic core of the enzyme. V279F causes a tilt on the axis of the mutation bearing helix to avoid steric clashes with the hydrophobic residues on the β-sheets adjacent to it, inducing subtle conformational changes on the H5-β 8 loop, β 8 sheet, and the loop bearing Asp296. A cascade of conformational changes induces a change in the orientation of His351 resulting in loss of hydrogen bonded interaction with catalytic Ser273. Q281R causes a shortening of H5 and β 8, which induces conformational changes of the loops bearing Ser273 and Asp296, respectively. Simultaneous conformational changes of secondary structural elements result in the flipping of His351 causing a break in the catalytic triad. Also, there is a compromise in the substrate-binding area and volume in the mutants resulting in loss of binding to its substrate.Conclusion: Mutant enzymes show changes at the site of the mutation, secondary motif conformations and global structural conformations that adversely affect the active site, decrease substrate channel volume and decrease stability, thereby affecting enzymatic function.Keywords: platelet activating factor acetyl hydrolase, structure, molecular modelling, mutations, V279F, Q281R, clinical phenotype, coronary artery disease
format	article
author	Khan MI Hariprasad G
author_facet	Khan MI Hariprasad G
author_sort	Khan MI
title	Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme
title_short	Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme
title_full	Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme
title_fullStr	Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme
title_full_unstemmed	Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme
title_sort	structural modeling of wild and mutant forms of human plasma platelet activating factor-acetyl hydrolase enzyme
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/154d4218684746ba8238f04ee62d49b2
work_keys_str_mv	AT khanmi structuralmodelingofwildandmutantformsofhumanplasmaplateletactivatingfactoracetylhydrolaseenzyme AT hariprasadg structuralmodelingofwildandmutantformsofhumanplasmaplateletactivatingfactoracetylhydrolaseenzyme
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Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme

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