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71.
Spencer J Read J Sessions RB Howell S Blackburn GM Gamblin SJ 《Journal of the American Chemical Society》2005,127(41):14439-14444
Metallo-beta-lactamases are zinc-dependent enzymes responsible for resistance to beta-lactam antibiotics in a variety of host bacteria, usually Gram-negative species that act as opportunist pathogens. They hydrolyze all classes of beta-lactam antibiotics, including carbapenems, and escape the action of available beta-lactamase inhibitors. Efforts to develop effective inhibitors have been hampered by the lack of structural information regarding how these enzymes recognize and turn over beta-lactam substrates. We report here the crystal structure of the Stenotrophomonas maltophilia L1 enzyme in complex with the hydrolysis product of the 7alpha-methoxyoxacephem, moxalactam. The on-enzyme complex is a 3'-exo-methylene species generated by elimination of the 1-methyltetrazolyl-5-thiolate anion from the 3'-methyl group. Moxalactam binding to L1 involves direct interaction of the two active site zinc ions with the beta-lactam amide and C4 carboxylate, groups that are common to all beta-lactam substrates. The 7beta-[(4-hydroxyphenyl)malonyl]-amino substituent makes limited hydrophobic and hydrogen bonding contacts with the active site groove. The mode of binding provides strong evidence that a water molecule situated between the two metal ions is the most likely nucleophile in the hydrolytic reaction. These data suggest a reaction mechanism for metallo-beta-lactamases in which both metal ions contribute to catalysis by activating the bridging water/hydroxide nucleophile, polarizing the substrate amide bond for attack and stabilizing anionic nitrogen intermediates. The structure illustrates how a binuclear zinc site confers upon metallo-beta-lactamases the ability both to recognize and efficiently hydrolyze a wide variety of beta-lactam substrates. 相似文献
72.
G. Michael Blackburn Andrew S. Cumming Graham E. Taylor 《Phosphorus, sulfur, and silicon and the related elements》2013,188(3-4)
Abstract We have previously established that the α-fluorination of alkanephosphonates provides analogues of phosphate esters which have improved ‘isopolarity’ relative to simple alkanephosphonates.1 This property is manifest, inter alia, in enhanced acidity and in the upfield shift for the 31P n.m.r. resonance. Indeed, for a range of halomethanephosphonic acids we have found the relationship “δP=9.61 (pKa2 - 4.59) ppm” gives an excellent correlation between these parameters. In this context, the properties of CF2CIPO(OR)2 species, derived from the Michaelis-Becker reaction of dialkyl phosphonates with Freon 22, CF2Cl2, will be described. 相似文献
73.
74.
We revisit the interpretation of earlier low temperature experiments on Josephson junctions under the influence of applied microwaves. It was claimed that these experiments unambiguously established a quantum phenomenology with discrete levels in shallow wells of the washboard potential, and macroscopic quantum tunneling. We here apply the previously developed classical theory to a direct comparison with the original experimental observations, and we show that the experimental data can be accurately represented classically. Thus, our analysis questions the necessity of the earlier quantum mechanical interpretation. 相似文献
75.
Xiao B Jing C Wilson JR Walker PA Vasisht N Kelly G Howell S Taylor IA Blackburn GM Gamblin SJ 《Nature》2003,421(6923):652-656
Acetylation, phosphorylation and methylation of the amino-terminal tails of histones are thought to be involved in the regulation of chromatin structure and function. With just one exception, the enzymes identified in the methylation of specific lysine residues on histones (histone methyltransferases) belong to the SET family. The high-resolution crystal structure of a ternary complex of human SET7/9 with a histone peptide and cofactor reveals that the peptide substrate and cofactor bind on opposite surfaces of the enzyme. The target lysine accesses the active site of the enzyme and the S-adenosyl-l-methionine (AdoMet) cofactor by inserting its side chain into a narrow channel that runs through the enzyme, connecting the two surfaces. Here we show from the structure and from solution studies that SET7/9, unlike most other SET proteins, is exclusively a mono-methylase. The structure indicates the molecular basis of the specificity of the enzyme for the histone target, and allows us to propose a model for the methylation reaction that accounts for the role of many of the residues that are invariant across the SET family. 相似文献
76.
Berry SM Ralle M Low DW Blackburn NJ Lu Y 《Journal of the American Chemical Society》2003,125(29):8760-8768
Expressed protein ligation was used to replace the axial methionine of the blue copper protein azurin from Pseudomonas aeruginosa with unnatural amino acids. The highly conserved methionine121 residue was replaced with the isostructural amino acids norleucine (Nle) and selenomethionine (SeM). The UV-visible absorption, X- and Q-band EPR, and Cu EXAFS spectra of the variants are slightly perturbed from WT. All variants have a predominant S(Cys) to Cu(II) charge transfer band around 625 nm and narrow EPR hyperfine splittings. The Se EXAFS of the M121SeM variant is also reported. In contrast to the small spectral changes, the reduction potentials of M121SeM, M121Leu, and M121Nle are 25, 135, and 140 mV, respectively, higher than that of WT azurin. The use of unnatural amino acids allowed deconvolution of different factors affecting the reduction potentials of the blue copper center. A careful analysis of the WT azurin and its variants obtained in this work showed the large reduction potential variation was linearly correlated with the hydrophobicity of the axial ligand side chains. Therefore, hydrophobicity is the dominant factor in tuning the reduction potentials of blue copper centers by axial ligands. 相似文献
77.
78.
Matthew J. Langton Dr. Octavia A. Blackburn Dr. Thomas Lang Prof. Stephen Faulkner Prof. Paul D. Beer 《Angewandte Chemie (International ed. in English)》2014,53(43):11463-11466
The first anion‐templated synthesis of a lanthanide‐containing interlocked molecule is demonstrated by utilizing a nitrite anion to template initial pseudorotaxane formation. Subsequent stoppering of the interpenetrated assembly allows for the preparation of a lanthanide‐functionalized [2]rotaxane in high yield. Following removal of the nitrite anion template, the europium [2]rotaxane host is demonstrated to recognize and sense fluoride selectively. 相似文献
79.
80.
Abbott B Abbott R Adhikari R Ageev A Allen B Amin R Anderson SB Anderson WG Araya M Armandula H Ashley M Asiri F Aufmuth P Aulbert C Babak S Balasubramanian R Ballmer S Barish BC Barker C Barker D Barnes M Barr B Barton MA Bayer K Beausoleil R Belczynski K Bennett R Berukoff SJ Betzwieser J Bhawal B Bilenko IA Billingsley G Black E Blackburn K Blackburn L Bland B Bochner B Bogue L Bork R Bose S Brady PR Braginsky VB Brau JE Brown DA Bullington A Bunkowski A Buonanno A Burgess R Busby D 《Physical review letters》2005,94(18):181103
We place direct upper limits on the amplitude of gravitational waves from 28 isolated radio pulsars by a coherent multidetector analysis of the data collected during the second science run of the LIGO interferometric detectors. These are the first direct upper limits for 26 of the 28 pulsars. We use coordinated radio observations for the first time to build radio-guided phase templates for the expected gravitational-wave signals. The unprecedented sensitivity of the detectors allows us to set strain upper limits as low as a few times 10(-24). These strain limits translate into limits on the equatorial ellipticities of the pulsars, which are smaller than 10(-5) for the four closest pulsars. 相似文献