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Titolo:
Structure of the first-shell active site in metallolactamase: Effect of water ligands
Autore:
Krauss, M; Gilson, HSR; Gresh, N;
Indirizzi:
Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA Maryland Biotechnol Inst Rockville MD USA 20850 , Rockville, MD 20850 USA VeraChem LLC, Gaithersburg, MD 20878 USA VeraChem LLC Gaithersburg MD USA20878 em LLC, Gaithersburg, MD 20878 USA Univ Paris 05, UMR 8600 CNRS, U266 INSERM, Equipe Pharmacochim Mol & Cellulaire, F-75006 Paris, France Univ Paris 05 Paris France F-75006 l & Cellulaire, F-75006 Paris, France
Titolo Testata:
JOURNAL OF PHYSICAL CHEMISTRY B
fascicolo: 33, volume: 105, anno: 2001,
pagine: 8040 - 8049
SICI:
1520-6106(20010823)105:33<8040:SOTFAS>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
METALLO-BETA-LACTAMASE; COMPACT EFFECTIVE POTENTIALS; BLUE COPPER PROTEINS; EXPONENT BASIS-SETS; BACTEROIDES-FRAGILIS; BACILLUS-CEREUS; AB-INITIO; CRYSTAL-STRUCTURE; BINDING SITES; MECHANISM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Physical, Chemical & Earth Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Krauss, M Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, 9600 Gudelsky Dr, Rockville, MD 20850 USA Maryland Biotechnol Inst 9600 Gudelsky Dr Rockville MD USA 20850
Citazione:
M. Krauss et al., "Structure of the first-shell active site in metallolactamase: Effect of water ligands", J PHYS CH B, 105(33), 2001, pp. 8040-8049

Abstract

In this study we have examined the behavior of the first-shell active siteof metallolactamases as a function of water both bound directly as a zinc ligand and hydrogen bonded to protein-residue ligands in the active site and as a function of metal-metal distance. The inherent effective interactionenergy of the bimetallic metallolactamase active site is relatively flat between the metal cations. This leaves the metal-metal distance susceptible to both perturbations from environmental interactions and protonation of active-site residues. Although the crystal structure of the active site of the zinc lactamase from Bacteroides fragilis is the initial starting point for the structure optimizations, structures very different from the equilibrium crystal structure as well as details of the water hydrogen-bonding pattern in the active site are obtained. Structures with Zn-Zn distances >4 Angstrom, with each metal cation acting as the center of a separate complex, result when only the crystallographic water that is directly coordinated to the Zn is included in the representation of the active site. When more crystallographic waters are included, the structure remains essentially unchanged from the crystal structure. In addition, a class of structures with even shorter metal-metal distances is calculated with the active site cysteine and the hydroxide ion bound to both zinc cations. This class of conformationis low in energy and includes several hydrogen bonds between the active-site residues and surrounding waters. Protonation of the active site also yields a metal-metal distance either >4 A or comparable to that in the crystalstructure, depending on whether the proton is added to the bridging hydroxide or to the carboxylate of the aspartate 103 ligand. The Zn-O distances of an X-ray structure obtained at a pH of 5.6 agree with those of the activesite protonated at the hydroxide. The long-distance structure is the lowest in energy for the Zn-Zn enzyme; however, when zinc is substituted by cadmium, the long-distance structure becomes higher in energy because the cadmium cation does not polarize the ligated water as strongly as zinc. The lowest-energy structure for the Zn-Cd system is predicted to have the zinc bound at the site with three histidine ligands, in agreement with a recent experimental deduction. We suggest that structures that differ from the crystalstructure can play a role in the reaction or in the initial stages of metal binding, as indicated by the UV-visible spectrum observed in the cobalt-substituted enzyme. Water that is hydrogen bonded to the active site is alsobelieved to play an important role in the catalytic mechanism; one of the waters may function as the nucleophile.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 09:17:05