Zinc binding in proteins and solution: A simple but accurate nonbonded representation

Stote, Roland H.; Karplus, Martin

doi:10.1002/prot.340230104

Cited by 343 publications

(408 citation statements)

References 96 publications

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“…The models were then optimized by CHARMM (33), using a consistent GBSW implicit solvent model (34) based on the all-atom CHARMM22/CMAP force field (35). We used a simple method to consider zinc and protein interactions (36) and applied harmonic restraints between zinc and the histidine residues in the coordination site with a decreasing restraint constant gradually. After the optimization, we removed all the restraints and evaluated the potential and generalized born free energy for the system.…”

Section: Methodsmentioning

confidence: 99%

Structural basis for the autoprocessing of zinc metalloproteases in the thermolysin family

Gao

Wang²,

Yu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Thermolysin-like proteases (TLPs), a large group of zinc metalloproteases, are synthesized as inactive precursors. TLPs with a long propeptide (∼200 residues) undergo maturation following autoprocessing through an elusive molecular mechanism. We report the first two crystal structures for the autoprocessed complexes of a typical TLP, MCP-02. In the autoprocessed complex, Ala205 shifts upward by 33 Å from the previously covalently linked residue, His204, indicating that, following autocleavage of the peptide bond between His204 and Ala205, a large conformational change from the zymogen to the autoprocessed complex occurs. The eight N-terminal residues (residues Ala205-Gly212) of the catalytic domain form a new β-strand, nestling into two other β-strands. Simultaneously, the apparent T m of the autoprocessed complex increases 20°C compared to that of the zymogen. The stepwise degradation of the propeptide begins with two sequential cuttings at Ser49-Val50 and Gly57-Leu58, which lead to the disassembly of the propeptide and the formation of mature MCP-02. Our findings give new insights into the molecular mechanism of TLP maturation.zymogen conversion | zinc metalloproteases inhibition | intramolecular chaperone T he thermolysin (M4) family is comprised of a large number of zinc metalloproteases in the subclan MA(E), most of which have similar sequences and domain structures (1). The representative member of this family is thermolysin (EC 3.4.24.27), a 34.6-kDa thermostable metalloprotease secreted by Bacillus thermoproteolyticus (2). The amino acid sequence and the threedimensional structure of thermolysin were first determined in 1972 (3, 4). Since then, thermolysin and thermolysin-like proteases (TLPs) have been used as models in studying zinc metalloproteases (5, 6).TLPs are widely distributed in many species of microorganisms, and many TLPs are regarded as key pathogenesis factors that are responsible for some severe bacterial infections (7). For example, λ-toxin from Clostridium perfringens can degrade various human immune defense proteins (8). Vibriolysin from Vibrio vulnificus (9) and pseudolysin from Pseudomonas aeruginosa (10) can be lethally blood-poisonous to humans. Therefore, understanding the catalytic and maturation mechanisms of TLPs is very important for developing therapeutics to treat such infectious diseases.TLPs are synthesized as a precursor with a propeptide. TLPs are divided into two distinct groups according to the primary structure of their propeptides. Less than 30% of the total TLPs have short propeptides (∼50 residues), and more than 70% of TLPs have long propeptides (∼200 residues) (11, 12). The long propeptide in TLPs contains two distinguished regions of conservation: an FTP (fungalysin/thermolysin propeptide) domain and a PepSY [peptidase propeptide and YPEB (a protein encoded by Bacillus subtilis ypeB gene)] domain. To date, the PepSY domain has been found not only in TLPs, but also in many nonpeptidase proteins, wherein the presence of this domain may prevent detrimental protease ...

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Section: Methodsmentioning

confidence: 99%

Structural basis for the autoprocessing of zinc metalloproteases in the thermolysin family

Gao

Wang²,

Yu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…A non-bonded approached was used for the metal ions [40,41]. Zinc was assigned a formal charge of +2.0, van der Waal's radius 0.69Å and well depth ε = 0.014 kcal/mol.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

Sjøli

Nuti

Camodeca

et al. 2016

European Journal of Medicinal Chemistry

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Enzymes of the M4 family of zinc-metalloproteinases are virulence factors secreted from grampositive or gram-negative bacteria, and putative drug targets in the treatment of bacterial infections. In order to have a therapeutic value such inhibitors should not interfere with endogenous zinc-metalloproteinases. In the present study we have synthesised a series of hydroxamate derivatives and validated the compounds as inhibitors of the M4 enzymes thermolysin and pseudolysin, and the endogenous metalloproteinases ADAM-17, MMP-2 and MMP-9 using experimental binding studies and molecular modelling. In general, the compounds are stronger inhibitors of the MMPs than of the M4 enzymes, however, an interesting exception is LM2. The compounds bound stronger to pseudolysin than to thermolysin, and the molecular modelling studies showed that occupation of the S2 ' subpocket by an aromatic group is favourable for strong interactions with pseudolysin.

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“…93,95,96 The simplest approach is a non-bonded model, in which no bonds between the metal and the ligands are defined. 97 However, such a model typically gives rather poor results and there is a great risk that the ligands may dissociate from the metal and other ligands may bind during the MD simulations. 98 Therefore, it is more common that metal sites are treated by a bonded model, in which the bonds between the metal and its ligands are treated the same way as covalent bonds within the protein, i.e.…”

Section: Parametrisationmentioning

confidence: 99%

Reorganization Energy for Internal Electron Transfer in Multicopper Oxidases

Farrokhnia

Heimdal

et al. 2011

J. Phys. Chem. B

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We have calculated the reorganisation energy for the intramolecular electron transfer between the reduced type 1 copper site and the peroxy intermediate of the trinuclear cluster in the multicopper oxidase CueO. The calculations are performed at the combined quantum mechanics and molecular mechanics (QM/MM) level, based on molecular dynamics simulations with tailored potentials for the two copper sites. We obtain a reorganisation energy of 91-133 kJ/mol, depending on the theoretical treatment. The two Cu sites contribute by 12 and 22 kJ/mol to this energy, whereas the solvent contribution is 34 kJ/mol. The rest comes from the protein, involving small contributions from many residues. We have also estimated the energy difference between the two electron-transfer states and show that the reduction of the peroxy intermediate is exergonic by 43-87 kJ/mol, depending on the theoretical method. Both the solvent and the protein contribute to this energy difference, especially charged residues close to the two Cu sites. We compare these estimates with energies obtained from QM/MM optimisations and QM calculations in vacuum, and discuss differences between the results obtained at various levels of theory.

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Zinc binding in proteins and solution: A simple but accurate nonbonded representation

Cited by 343 publications

References 96 publications

Structural basis for the autoprocessing of zinc metalloproteases in the thermolysin family

Structural basis for the autoprocessing of zinc metalloproteases in the thermolysin family

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

Reorganization Energy for Internal Electron Transfer in Multicopper Oxidases

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