Quantum Chemistry Study on the Interaction of the Exogenous Ligands and the Catalytic Zinc Ion in Matrix Metalloproteinases

2002 ◽  
Vol 106 (17) ◽  
pp. 4552-4559 ◽  
Author(s):  
Feng Cheng ◽  
Ruihao Zhang ◽  
Xiaomin Luo ◽  
Jianhua Shen ◽  
Xin Li ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Quantum Chemistry ◽  
Zinc Ion ◽  
Exogenous Ligands ◽  
Catalytic Zinc

THEORETICAL STUDIES ON INTERACTION MECHANISMS BETWEEN EMODIN OF ANTHRAQUINONES AND CATALYTIC ZINC ION IN MATRIX METALLOPROTEINASES

2013 ◽  
Vol 12 (04) ◽  
pp. 1350023 ◽  
Author(s):  
JI ZHANG ◽  
JIAN ZU ◽  
PEI CHEN ◽  
DANNI YU ◽  
YAN YANG ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Matrix Metalloproteinases ◽  
Carbonyl Group ◽  
Biological Activities ◽  
Zinc Ion ◽  
Exchange Reactions ◽  
Interaction Mechanisms ◽  
Quantum Chemistry Calculations ◽  
Hydroxy Groups ◽  
Catalytic Zinc

Quantum chemistry calculations together with modeling of ligand–water exchange reactions are used to investigate, for the first time, the interaction mechanisms between emodin of anthraquinones and the catalytic zinc ion in matrix metalloproteinases (MMPs), and the coordinating mode between them is determined. The calculations indicate that the electron transfer from the emodin molecule to the catalytic zinc ion in MMPs occurs when the catalytic zinc ion coordinates with the O atoms of substituent groups at various positions of emodin molecule, and the more the number of the electron transfer from the coordinating O atom of substituent group of emodin molecule to the catalytic zinc ion, the stronger the coordinating ability between them. It is found that comparing with the O atoms of hydroxy groups at 1-position, 8-position and 3-position and the O atom of carbonyl group at 9-position of emodin molecule, the coordinating ability for the O atom of carbonyl group at 10-position of emodin molecule with the catalytic zinc ion in MMPs is the strongest. Therefore, when emodin inhibits MMPs activity, the catalytic zinc ion in MMPs should coordinate with the carbonyl group at 10-position of emodin molecule, rather than the hydroxy groups and carbonyl group at its other positions. Our calculated results are in agreement with previous relevant experimental results. This paper may be helpful for designing the new MMPs inhibitors having higher biological activities by carrying out the structural modifications of emodin molecule.

Matrix metalloproteinases: structure, functions and genetic polymorphism

2017 ◽  
pp. 14-23
Author(s):  
А.С. Шадрина ◽  
И.В. Терешкина ◽  
Я.З. Плиева ◽  
Д.Н. Кушлинский ◽  
Д.О. Уткин ◽  
...  
Keyword(s):  
Genetic Polymorphism ◽  
Matrix Metalloproteinases ◽  
Active Center ◽  
Human Body ◽  
Enzymatic Catalysis ◽  
Structure Functions ◽  
Zinc Ion ◽  
Etiological Factors ◽  
Mmp Genes

Матриксные металлопротеиназы (ММП) - ферменты класса гидролаз, осуществляющие ферментативный катализ с помощью связанного в активном центре иона цинка. Функции ММП разнообразны, и нарушение баланса их активности может быть одним из этиологических факторов различных заболеваний. В данном обзоре рассмотрена классификация ММП человека, особенности их структуры и регуляции, а также роль в физиологических и патологических процессах в организме человека. Приведен перечень наиболее изученных на настоящий момент полиморфных вариантов генов MMП, описаны их функциональные эффекты и представлены результаты ассоциативных исследований. Matrix metalloproteinases (MMPs) are enzymes of the hydrolase class that carry out enzymatic catalysis with the help of a zinc ion bound in the active center. MMP functions are diverse, and a disturbance in the balance of their activity may be one of the etiological factors of various diseases. In this review, the classification of human MMP, the features of their structure and regulation, as well as the role in physiological and pathological processes in the human body are considered. A list of the most studied polymorphic versions of MMP genes has been given, their functional effects have been described, and the results of associative studies have been presented.

scholarly journals Probing the Role of Divalent Metal Ions in a Bacterial Psychrophilic Metalloprotease: Binding Studies of an Enzyme in the Crystalline State by X-Ray Crystallography

2003 ◽  
Vol 185 (14) ◽  
pp. 4195-4203 ◽  
Author(s):  
Stephanie Ravaud ◽  
Patrice Gouet ◽  
Richard Haser ◽  
Nushin Aghajari
Keyword(s):  
Metal Ions ◽  
Calcium Ions ◽  
Calcium Ion ◽  
Crystalline State ◽  
Zinc Ion ◽  
Binding Studies ◽  
X Ray ◽  
X Ray Crystallography ◽  
Catalytic Zinc

ABSTRACT The psychrophilic alkaline metalloprotease (PAP) produced by a Pseudomonas bacterium isolated in Antarctica belongs to the clan of metzincins, for which a zinc ion is essential for catalytic activity. Binding studies in the crystalline state have been performed by X-ray crystallography in order to improve the understanding of the role of the zinc and calcium ions bound to this protease. Cocrystallization and soaking experiments with EDTA in a concentration range from 1 to 85 mM have resulted in five three-dimensional structures with a distinct number of metal ions occupying the ion-binding sites. Evolution of the structural changes observed in the vicinity of each cation-binding site has been studied as a function of the concentration of EDTA, as well as of time, in the presence of the chelator. Among others, we have found that the catalytic zinc ion was the first ion to be chelated, ahead of a weakly bound calcium ion (Ca 700) exclusive to the psychrophilic enzyme. Upon removal of the catalytic zinc ion, the side chains of the active-site residues His-173, His-179 and Tyr-209 shifted ∼4, 1.0, and 1.6 Å, respectively. Our studies confirm and also explain the sensitivity of PAP toward moderate EDTA concentrations and propose distinct roles for the calcium ions. A new crystal form of native PAP validates our previous predictions regarding the adaptation of this enzyme to cold environments as well as the proteolytic domain calcium ion being exclusive for PAP independent of crystallization conditions.

Reaction mechanism of matrix metalloproteinases with a catalytically active zinc ion studied by the QM(DFTB)/MM simulations

2016 ◽  
Vol 26 (3) ◽  
pp. 209-211 ◽  
Author(s):  
Tatiana Vasilevskaya ◽  
Maria G. Khrenova ◽  
Alexander V. Nemukhin ◽  
Walter Thiel
Keyword(s):  
Reaction Mechanism ◽  
Matrix Metalloproteinases ◽  
Zinc Ion ◽  
Catalytically Active

scholarly journals Structural and Functional Analysis of the Complex between Citrate and the Zinc Peptidase Carboxypeptidase A

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Daniel Fernández ◽  
Ester Boix ◽  
Irantzu Pallarès ◽  
Francesc X. Avilés ◽  
Josep Vendrell
Keyword(s):  
Oral Delivery ◽  
Binding Mode ◽  
Competitive Inhibitor ◽  
Zinc Ion ◽  
X Ray Diffraction ◽  
Carboxypeptidase A ◽  
X Ray ◽  
Citrate Complex ◽  
First Time ◽  
Catalytic Zinc

A high-resolution carboxypeptidase-Zn2+-citrate complex was studied by X-ray diffraction and enzyme kinetics for the first time. The citrate molecule acts as a competitive inhibitor of this benchmark zinc-dependent peptidase, chelating the catalytic zinc ion in the active site of the enzyme and inducing a conformational change such that carboxypeptidase adopts the conformation expected to occur by substrate binding. Citrate adopts an extended conformation with half of the molecule facing the zinc ion, while the other half is docked in the S1′ hydrophobic specificity pocket of the enzyme, in contrast with the binding mode expected for a substrate like phenylalanine or a peptidomimetic inhibitor like benzylsuccinic acid. Combined structural and enzymatic analysis describes the characteristics of the binding of this ligand that, acting against physiologically relevant zinc-dependent proteases, may serve as a general model in the design of new drug-protecting molecules for the oral delivery of drugs of peptide origin.

scholarly journals Structure-based mechanism of cysteine-switch latency and of catalysis by pappalysin-family metallopeptidases

IUCrJ ◽  
2020 ◽  
Vol 7 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Tibisay Guevara ◽  
Arturo Rodriguez-Banqueri ◽  
Miroslaw Ksiazek ◽  
Jan Potempa ◽  
F. Xavier Gomis-Rüth
Keyword(s):  
Catalytic Domain ◽  
Front Surface ◽  
Zinc Ion ◽  
Methanosarcina Acetivorans ◽  
Active Site Cleft ◽  
Switch Mechanism ◽  
Mature Enzyme ◽  
Catalytic Zinc ◽  
Matrix Metallopeptidases ◽  
Cysteine Switch

Tannerella forsythia is an oral dysbiotic periodontopathogen involved in severe human periodontal disease. As part of its virulence factor armamentarium, at the site of colonization it secretes mirolysin, a metallopeptidase of the unicellular pappalysin family, as a zymogen that is proteolytically auto-activated extracellularly at the Ser54–Arg55 bond. Crystal structures of the catalytically impaired promirolysin point mutant E225A at 1.4 and 1.6 Å revealed that latency is exerted by an N-terminal 34-residue pro-segment that shields the front surface of the 274-residue catalytic domain, thus preventing substrate access. The catalytic domain conforms to the metzincin clan of metallopeptidases and contains a double calcium site, which acts as a calcium switch for activity. The pro-segment traverses the active-site cleft in the opposite direction to the substrate, which precludes its cleavage. It is anchored to the mature enzyme through residue Arg21, which intrudes into the specificity pocket in cleft sub-site S1′. Moreover, residue Cys23 within a conserved cysteine–glycine motif blocks the catalytic zinc ion by a cysteine-switch mechanism, first described for mammalian matrix metallopeptidases. In addition, a 1.5 Å structure was obtained for a complex of mature mirolysin and a tetradecapeptide, which filled the cleft from sub-site S1′ to S6′. A citrate molecule in S1 completed a product-complex mimic that unveiled the mechanism of substrate binding and cleavage by mirolysin, the catalytic domain of which was already preformed in the zymogen. These results, including a preference for cleavage before basic residues, are likely to be valid for other unicellular pappalysins derived from archaea, bacteria, cyanobacteria, algae and fungi, including archetypal ulilysin from Methanosarcina acetivorans. They may further apply, at least in part, to the multi-domain orthologues of higher organisms.

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