Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9

Abstract MMP-9 plays a number of important physiological functions but is also responsible for many pathological processes, including cancer invasion, metastasis, and angiogenesis. It is, therefore, crucial to understand its enzymatic activity, including activation and inhibition mechanisms. This en...

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Autores principales:	Łukasz Charzewski, Krystiana A. Krzyśko, Bogdan Lesyng
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/31d6a2a981a641369c72f07ab9878909
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spelling	oai:doaj.org-article:31d6a2a981a641369c72f07ab98789092021-12-02T18:18:58ZStructural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-910.1038/s41598-021-92881-x2045-2322https://doaj.org/article/31d6a2a981a641369c72f07ab98789092021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92881-xhttps://doaj.org/toc/2045-2322Abstract MMP-9 plays a number of important physiological functions but is also responsible for many pathological processes, including cancer invasion, metastasis, and angiogenesis. It is, therefore, crucial to understand its enzymatic activity, including activation and inhibition mechanisms. This enzyme may also be partially involved in the “cytokine storm” that is characteristic of COVID-19 disease (SARS-CoV-2), as well as in the molecular mechanisms responsible for lung fibrosis. Due to the variety of processing pathways involving MMP-9 in biological systems and its uniqueness due to the O-glycosylated domain (OGD) and fibronectin-like (FBN) domain, specific interactions with its natural TIMP-1 inhibitor should be carefully studied, because they differ significantly from other homologous systems. In particular, earlier experimental studies have indicated that the newly characterised circular form of a proMMP-9 homotrimer exhibits stronger binding properties to TIMP-1 compared to its monomeric form. However, molecular structures of the complexes and the binding mechanisms remain unknown. The purpose of this study is to fill in the gaps in knowledge. Molecular modelling methods are applied to build the inhibitory and non-inhibitory MMP-9–TIMP-1 complexes, which allows for a detailed description of these structures and should allow for a better understanding of the regulatory processes in which MMP-9 is involved.Łukasz CharzewskiKrystiana A. KrzyśkoBogdan LesyngNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Łukasz Charzewski Krystiana A. Krzyśko Bogdan Lesyng Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9
description	Abstract MMP-9 plays a number of important physiological functions but is also responsible for many pathological processes, including cancer invasion, metastasis, and angiogenesis. It is, therefore, crucial to understand its enzymatic activity, including activation and inhibition mechanisms. This enzyme may also be partially involved in the “cytokine storm” that is characteristic of COVID-19 disease (SARS-CoV-2), as well as in the molecular mechanisms responsible for lung fibrosis. Due to the variety of processing pathways involving MMP-9 in biological systems and its uniqueness due to the O-glycosylated domain (OGD) and fibronectin-like (FBN) domain, specific interactions with its natural TIMP-1 inhibitor should be carefully studied, because they differ significantly from other homologous systems. In particular, earlier experimental studies have indicated that the newly characterised circular form of a proMMP-9 homotrimer exhibits stronger binding properties to TIMP-1 compared to its monomeric form. However, molecular structures of the complexes and the binding mechanisms remain unknown. The purpose of this study is to fill in the gaps in knowledge. Molecular modelling methods are applied to build the inhibitory and non-inhibitory MMP-9–TIMP-1 complexes, which allows for a detailed description of these structures and should allow for a better understanding of the regulatory processes in which MMP-9 is involved.
format	article
author	Łukasz Charzewski Krystiana A. Krzyśko Bogdan Lesyng
author_facet	Łukasz Charzewski Krystiana A. Krzyśko Bogdan Lesyng
author_sort	Łukasz Charzewski
title	Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9
title_short	Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9
title_full	Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9
title_fullStr	Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9
title_full_unstemmed	Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9
title_sort	structural characterisation of inhibitory and non-inhibitory mmp-9–timp-1 complexes and implications for regulatory mechanisms of mmp-9
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/31d6a2a981a641369c72f07ab9878909
work_keys_str_mv	AT łukaszcharzewski structuralcharacterisationofinhibitoryandnoninhibitorymmp9timp1complexesandimplicationsforregulatorymechanismsofmmp9 AT krystianaakrzysko structuralcharacterisationofinhibitoryandnoninhibitorymmp9timp1complexesandimplicationsforregulatorymechanismsofmmp9 AT bogdanlesyng structuralcharacterisationofinhibitoryandnoninhibitorymmp9timp1complexesandimplicationsforregulatorymechanismsofmmp9
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Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9

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