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Article: A Distal Disulfide Bridge in OXA-1 Î²-Lactamase Stabilizes the Catalytic Center and Alters the Dynamics of the Specificity Determining Î© Loop

Simakov, Nikolay / Leonard David A / Smith Jeremy C / Wymore Troy / Szarecka Agnieszka

Journal of physical chemistry. 2017 Apr. 20, v. 121, no. 15

2017

Abstract: Widespread antibiotic resistance, particularly when mediated by broad-spectrum Î²-lactamases, has major implications for public health. Substitutions in the active site often allow broad-spectrum enzymes to accommodate diverse types of Î²-lactams. ... ...

Abstract	Widespread antibiotic resistance, particularly when mediated by broad-spectrum Î²-lactamases, has major implications for public health. Substitutions in the active site often allow broad-spectrum enzymes to accommodate diverse types of Î²-lactams. Substitutions observed outside the active site are thought to compensate for the loss of thermal stability. The OXA-1 clade of class D Î²-lactamases contains a pair of conserved cysteines located outside the active site that forms a disulfide bond in the periplasm. Here, the effect of the distal disulfide bond on the structure and dynamics of OXA-1 was investigated via 4 Î¼s molecular dynamics simulations. The results reveal that the disulfide promotes the preorganized orientation of the catalytic residues and affects the conformation of the functionally important Î© loop. Furthermore, principal component analysis reveals differences in the global dynamics between the oxidized and reduced forms, especially in the motions involving the Î© loop. A dynamical network analysis indicates that, in the oxidized form, in addition to its role in ligand binding, the KTG family motif is a central hub of the global dynamics. As activity of OXA-1 has been measured only in the reduced form, we suggest that accurate assessment of its functional profile would require oxidative conditions mimicking periplasm.
Keywords	active sites ; antibiotic resistance ; beta-lactamase ; beta-lactams ; disulfide bonds ; ligands ; molecular dynamics ; principal component analysis ; public health ; thermal stability
Language	English
Dates of publication	2017-0420
Size	p. 3285-3296.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5207
DOI	10.1021%2Facs.jpcb.6b07884
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A Distal Disulfide Bridge in OXA-1 β-Lactamase Stabilizes the Catalytic Center and Alters the Dynamics of the Specificity Determining Ω Loop.

Simakov, Nikolay / Leonard, David A / Smith, Jeremy C / Wymore, Troy / Szarecka, Agnieszka

The journal of physical chemistry. B

2017 Volume 121, Issue 15, Page(s) 3285–3296

Abstract: Widespread antibiotic resistance, particularly when mediated by broad-spectrum β-lactamases, has major implications for public health. Substitutions in the active site often allow broad-spectrum enzymes to accommodate diverse types of β-lactams. ... ...

Abstract	Widespread antibiotic resistance, particularly when mediated by broad-spectrum β-lactamases, has major implications for public health. Substitutions in the active site often allow broad-spectrum enzymes to accommodate diverse types of β-lactams. Substitutions observed outside the active site are thought to compensate for the loss of thermal stability. The OXA-1 clade of class D β-lactamases contains a pair of conserved cysteines located outside the active site that forms a disulfide bond in the periplasm. Here, the effect of the distal disulfide bond on the structure and dynamics of OXA-1 was investigated via 4 μs molecular dynamics simulations. The results reveal that the disulfide promotes the preorganized orientation of the catalytic residues and affects the conformation of the functionally important Ω loop. Furthermore, principal component analysis reveals differences in the global dynamics between the oxidized and reduced forms, especially in the motions involving the Ω loop. A dynamical network analysis indicates that, in the oxidized form, in addition to its role in ligand binding, the KTG family motif is a central hub of the global dynamics. As activity of OXA-1 has been measured only in the reduced form, we suggest that accurate assessment of its functional profile would require oxidative conditions mimicking periplasm.
Language	English
Publishing date	2017-04-20
Publishing country	United States
Document type	Journal Article
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.6b07884
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Article: Optimization of the GB/SA solvation model for predicting the structure of surface loops in proteins.

Szarecka, Agnieszka / Meirovitch, Hagai

The journal of physical chemistry. B

2006 Volume 110, Issue 6, Page(s) 2869–2880

Abstract: Implicit solvation models are commonly optimized with respect to experimental data or Poisson-Boltzmann (PB) results obtained for small molecules, where the force field is sometimes not considered. In previous studies, we have developed an optimization ... ...

Abstract	Implicit solvation models are commonly optimized with respect to experimental data or Poisson-Boltzmann (PB) results obtained for small molecules, where the force field is sometimes not considered. In previous studies, we have developed an optimization procedure for cyclic peptides and surface loops in proteins based on the entire system studied and the specific force field used. Thus, the loop has been modeled by the simplified solvation function E(tot) = E(FF) (epsilon = 2r) + Sigma(i) sigma(i)A(i), where E(FF) (epsilon = nr) is the AMBER force field energy with a distance-dependent dielectric function, epsilon = nr, A(i) is the solvent accessible surface area of atom i, and sigma(i) is its atomic solvation parameter. During the optimization process, the loop is free to move while the protein template is held fixed in its X-ray structure. To improve on the results of this model, in the present work we apply our optimization procedure to the physically more rigorous solvation model, the generalized Born with surface area (GB/SA) (together with the all-atom AMBER force field) as suggested by Still and co-workers (J. Phys. Chem. A 1997, 101, 3005). The six parameters of the GB/SA model, namely, P(1)-P(5) and the surface area parameter, sigma (programmed in the TINKER package) are reoptimized for a "training" group of nine loops, and a best-fit set is defined from the individual sets of optimized parameters. The best-fit set and Still's original set of parameters (where Lys, Arg, His, Glu, and Asp are charged or neutralized) were applied to the training group as well as to a "test" group of seven loops, and the energy gaps and the corresponding RMSD values were calculated. These GB/SA results based on the three sets of parameters have been found to be comparable; surprisingly, however, they are somewhat inferior (e.g, of larger energy gaps) to those obtained previously from the simplified model described above. We discuss recent results for loops obtained by other solvation models and potential directions for future studies.
MeSH term(s)	Models, Biological ; Protein Structure, Tertiary ; Proteins/chemistry ; Surface Properties
Chemical Substances	Proteins
Language	English
Publishing date	2006-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1520-6106
ISSN	1520-6106
DOI	10.1021/jp055771+
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Article ; Online: Crosslinking constraints and computational models as complementary tools in modeling the extracellular domain of the glycine receptor.

Liu, Zhenyu / Szarecka, Agnieszka / Yonkunas, Michael / Speranskiy, Kirill / Kurnikova, Maria / Cascio, Michael

PloS one

2014 Volume 9, Issue 7, Page(s) e102571

Abstract: The glycine receptor (GlyR), a member of the pentameric ligand-gated ion channel superfamily, is the major inhibitory neurotransmitter-gated receptor in the spinal cord and brainstem. In these receptors, the extracellular domain binds agonists, ... ...

Abstract	The glycine receptor (GlyR), a member of the pentameric ligand-gated ion channel superfamily, is the major inhibitory neurotransmitter-gated receptor in the spinal cord and brainstem. In these receptors, the extracellular domain binds agonists, antagonists and various other modulatory ligands that act allosterically to modulate receptor function. The structures of homologous receptors and binding proteins provide templates for modeling of the ligand-binding domain of GlyR, but limitations in sequence homology and structure resolution impact on modeling studies. The determination of distance constraints via chemical crosslinking studies coupled with mass spectrometry can provide additional structural information to aid in model refinement, however it is critical to be able to distinguish between intra- and inter-subunit constraints. In this report we model the structure of GlyBP, a structural and functional homolog of the extracellular domain of human homomeric α1 GlyR. We then show that intra- and intersubunit Lys-Lys crosslinks in trypsinized samples of purified monomeric and oligomeric protein bands from SDS-polyacrylamide gels may be identified and differentiated by MALDI-TOF MS studies of limited resolution. Thus, broadly available MS platforms are capable of providing distance constraints that may be utilized in characterizing large complexes that may be less amenable to NMR and crystallographic studies. Systematic studies of state-dependent chemical crosslinking and mass spectrometric identification of crosslinked sites has the potential to complement computational modeling efforts by providing constraints that can validate and refine allosteric models.
MeSH term(s)	Amino Acid Sequence ; Animals ; Bacterial Proteins/chemistry ; Cross-Linking Reagents/chemistry ; Dimethyl Suberimidate/chemistry ; Hydrogen Bonding ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Subunits/chemistry ; Receptors, Glycine/chemistry ; Sf9 Cells ; Spodoptera ; Structural Homology, Protein
Chemical Substances	Bacterial Proteins ; Cross-Linking Reagents ; Protein Subunits ; Receptors, Glycine ; Dimethyl Suberimidate (29878-26-0)
Language	English
Publishing date	2014-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0102571
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Article ; Online: Clinical Variants of the Native Class D β-Lactamase of Acinetobacter baumannii Pose an Emerging Threat through Increased Hydrolytic Activity against Carbapenems.

Schroder, Emma C / Klamer, Zachary L / Saral, Aysegul / Sugg, Kyle A / June, Cynthia M / Wymore, Troy / Szarecka, Agnieszka / Leonard, David A

Antimicrobial agents and chemotherapy

2016 Volume 60, Issue 10, Page(s) 6155–6164

Abstract: The threat posed by the chromosomally encoded class D β-lactamase of Acinetobacter baumannii (OXA-51/66) has been unclear, in part because of its relatively low affinity and turnover rate for carbapenems. Several hundred clinical variants of OXA-51/66 ... ...

Abstract	The threat posed by the chromosomally encoded class D β-lactamase of Acinetobacter baumannii (OXA-51/66) has been unclear, in part because of its relatively low affinity and turnover rate for carbapenems. Several hundred clinical variants of OXA-51/66 have been reported, many with substitutions of active-site residues. We determined the kinetic properties of OXA-66 and five clinical variants with respect to a wide variety of β-lactam substrates. The five variants displayed enhanced activity against carbapenems and in some cases against penicillins, late-generation cephalosporins, and the monobactam aztreonam. Molecular dynamics simulations show that in OXA-66, P130 inhibits the side-chain rotation of I129 and thereby prevents doripenem binding because of steric clash. A single amino acid substitution at this position (P130Q) in the variant OXA-109 greatly enhances the mobility of both I129 and a key active-site tryptophan (W222), thereby facilitating carbapenem binding. This expansion of substrate specificity represents a very worrisome development for the efficacy of β-lactams against this troublesome pathogen.
MeSH term(s)	Acinetobacter baumannii/drug effects ; Acinetobacter baumannii/genetics ; Acinetobacter baumannii/isolation & purification ; Amino Acid Substitution ; Carbapenems/metabolism ; Carbapenems/pharmacology ; Catalytic Domain ; Humans ; Hydrolysis ; Molecular Dynamics Simulation ; Protein Conformation ; Substrate Specificity ; beta-Lactam Resistance ; beta-Lactamases/chemistry ; beta-Lactamases/genetics ; beta-Lactamases/metabolism
Chemical Substances	Carbapenems ; beta-Lactamases (EC 3.5.2.6) ; beta-lactamase OXA-51, Acinetobacter baumannii (EC 3.5.2.6)
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01277-16
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Article ; Online: The structure of a doripenem-bound OXA-51 class D β-lactamase variant with enhanced carbapenemase activity.

June, Cynthia M / Muckenthaler, Taylor J / Schroder, Emma C / Klamer, Zachary L / Wawrzak, Zdzislaw / Powers, Rachel A / Szarecka, Agnieszka / Leonard, David A

Protein science : a publication of the Protein Society

2016 Volume 25, Issue 12, Page(s) 2152–2163

Abstract: OXA-51 is a class D β-lactamase that is thought to be the native carbapenemase of Acinetobacter baumannii. Many variants of OXA-51 containing active site substitutions have been identified from A. baumannii isolates, and some of these substitutions ... ...

Abstract	OXA-51 is a class D β-lactamase that is thought to be the native carbapenemase of Acinetobacter baumannii. Many variants of OXA-51 containing active site substitutions have been identified from A. baumannii isolates, and some of these substitutions increase hydrolytic activity toward carbapenem antibiotics. We have determined the high-resolution structures of apo OXA-51 and OXA-51 with one such substitution (I129L) with the carbapenem doripenem trapped in the active site as an acyl-intermediate. The structure shows that acyl-doripenem adopts an orientation very similar to carbapenem ligands observed in the active site of OXA-24/40 (doripenem) and OXA-23 (meropenem). In the OXA-51 variant/doripenem complex, the indole ring of W222 is oriented away from the doripenem binding site, thereby eliminating a clash that is predicted to occur in wildtype OXA-51. Similarly, in the OXA-51 variant complex, L129 adopts a different rotamer compared to I129 in wildtype OXA-51. This alternative position moves its side chain away from the hydroxyethyl moiety of doripenem and relieves another potential clash between the enzyme and carbapenem substrates. Molecular dynamics simulations of OXA-51 and OXA-51 I129L demonstrate that compared to isoleucine, a leucine at this position greatly favors a rotamer that accommodates the ligand. These results provide a molecular justification for how this substitution generates enhanced binding affinity for carbapenems, and therefore helps explain the prevalence of this substitution in clinical OXA-51 variants.
MeSH term(s)	Acinetobacter baumannii/enzymology ; Acinetobacter baumannii/genetics ; Amino Acid Substitution ; Binding Sites ; Carbapenems/chemistry ; Crystallography, X-Ray ; Molecular Dynamics Simulation ; Mutation, Missense ; beta-Lactamases/chemistry ; beta-Lactamases/genetics
Chemical Substances	Carbapenems ; doripenem (BHV525JOBH) ; beta-Lactamases (EC 3.5.2.6) ; beta-lactamase OXA-51, Acinetobacter baumannii (EC 3.5.2.6)
Language	English
Publishing date	2016-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.3040
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Article: Dynamics of firefly luciferase inhibition by general anesthetics: Gaussian and anisotropic network analyses.

Szarecka, Agnieszka / Xu, Yan / Tang, Pei

Biophysical journal

2007 Volume 93, Issue 6, Page(s) 1895–1905

Abstract: The new crystal structures of the product-bound firefly luciferase combined with the previously determined substrate-free structures allow for a detailed analysis of the dynamics basis for the luciferase enzymatic activities. Using the Gaussian network ... ...

Abstract	The new crystal structures of the product-bound firefly luciferase combined with the previously determined substrate-free structures allow for a detailed analysis of the dynamics basis for the luciferase enzymatic activities. Using the Gaussian network model and the anisotropic network model, we show here that the superposition of the three slowest anisotropic network model modes, consisting of the bending, rotating, and rocking motions of the C-domain, accounts for large rearrangement of domains from the substrate-free (open) to product-bound (closed) conformation and thus constitutes a critical component of the enzyme's functions. The analysis also offers a unique platform to reexamine the molecular mechanism of the anesthetic inhibition of the firefly luciferase. Through perturbing the protein backbone network by introducing additional nodes to represent anesthetics, we found that the presence of two representative anesthetics, halothane and n-decanol, in different regions of luciferase had distinctively different effects on the protein's global motion. Only at the interface of the C- and N-domains did the anesthetics cause the most profound reduction in the overall flexibility of the C-domain and the concomitant increase in the flexibility of the loop, where the substitution of a conserved lysine residue was found experimentally to lead to >2-3 orders of magnitude reduction in activity. These anesthetic-induced dynamics changes can alter the normal function of the protein, appearing as an epiphenomenon of an "inhibition". The implication of the study is that a leading element for general anesthetic action on proteins is to disrupt the modes of motion essential to protein functions.
MeSH term(s)	Anesthetics, General/pharmacology ; Animals ; Anisotropy ; Binding Sites ; Biophysical Phenomena ; Biophysics ; Crystallography, X-Ray ; Fatty Alcohols/pharmacology ; Halothane/pharmacology ; In Vitro Techniques ; Luciferases, Firefly/antagonists & inhibitors ; Luciferases, Firefly/chemistry ; Models, Molecular ; Protein Conformation ; Protein Structure, Tertiary ; Thermodynamics
Chemical Substances	Anesthetics, General ; Fatty Alcohols ; n-decyl alcohol (89V4LX791F) ; Luciferases, Firefly (EC 1.13.12.7) ; Halothane (UQT9G45D1P)
Language	English
Publishing date	2007-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1529/biophysj.106.102780
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Article ; Online: Dynamics of heteropentameric nicotinic acetylcholine receptor: implications of the gating mechanism.

Szarecka, Agnieszka / Xu, Yan / Tang, Pei

Proteins

2007 Volume 68, Issue 4, Page(s) 948–960

Abstract: The dynamics characteristics of the currently available structure of Torpedo nicotinic acetylcholine receptor (nAChR), including the extracellular, transmembrane, and intracellular domains (ICDs), were analyzed using the Gaussian Network Model (GNM) and ... ...

Abstract	The dynamics characteristics of the currently available structure of Torpedo nicotinic acetylcholine receptor (nAChR), including the extracellular, transmembrane, and intracellular domains (ICDs), were analyzed using the Gaussian Network Model (GNM) and Anisotropic Network Model (ANM). We found that a symmetric quaternary twist motion, reported previously in the literature in a homopentameric receptor (Cheng et al. J Mol Biol 2006;355:310-324; Taly et al. Biophys J 2005;88:3954-3965), occurred also in the heteropentameric Torpedo nAChR. We believe, however, that the symmetric twist alone is not sufficient to explain a large body of experimental data indicating asymmetry and subunit nonequivalence during gating. Here we report our results supporting the hypothesis that a combination of symmetric and asymmetric motions opens the gate. We show that the asymmetric motion involves tilting of the TM2 helices. Furthermore, our study reveals three additional aspects of channel dynamics: (1) loop A serves as an allosteric mediator between the ligand binding loops and those at the domain interface, particularly the linker between TM2 and TM3; (2) the ICD can modulate the pore dynamics and thus should not be neglected in gating studies; and (3) the F loops, which are peculiarly longer and poorly-conserved in non-alpha-subunits, have important dynamical implications.
MeSH term(s)	Animals ; Elasticity ; Ion Channel Gating/physiology ; Models, Molecular ; Models, Theoretical ; Oligopeptides/chemistry ; Protein Conformation ; Protein Subunits/chemistry ; Receptors, Nicotinic/chemistry ; Receptors, Nicotinic/physiology ; Torpedo
Chemical Substances	Oligopeptides ; Protein Subunits ; Receptors, Nicotinic
Language	English
Publishing date	2007-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.21462
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Article ; Online: The Class D beta-lactamase family: residues governing the maintenance and diversity of function.

Szarecka, Agnieszka / Lesnock, Kimberly R / Ramirez-Mondragon, Carlos A / Nicholas, Hugh B / Wymore, Troy

Protein engineering, design & selection : PEDS

2011 Volume 24, Issue 10, Page(s) 801–809

Abstract: Class D β-lactamases, a major source of bacterial resistance to β-lactam antibiotic therapies, represent a distinct subset of the β-lactamase superfamily. They share a serine hydrolase mechanism with Classes A/C vs. Class B. Further understanding of ... ...

Abstract	Class D β-lactamases, a major source of bacterial resistance to β-lactam antibiotic therapies, represent a distinct subset of the β-lactamase superfamily. They share a serine hydrolase mechanism with Classes A/C vs. Class B. Further understanding of their sequence-structure-function relationships would benefit efforts to design a new generation of antibiotics as well as to predict evolutionary mechanisms in response to such therapies. Here we describe analyses based on our high-resolution multiple sequence alignment and phylogenetic tree of ∼80 Class D β-lactamases that leverage several 3D structures of these enzymes. We observe several sequence clusters on the phylogenetic tree, some that are species specific while others include several species from α-, β- and γ-proteobacteria. Residues characteristic of a specific cluster were identified and shown to be located just outside the active site, possibly modulating the function of the catalytic residues to facilitate reactions with specific types of β-lactams. Most significant was the discovery of a likely disulfide bond in a large group composed of α-, β- and γ-proteobacteria that would contribute to enzyme stability and hence bacterial viability under antibiotic assault. A network of co-evolving residues was identified which suggested the importance of maintaining a surface for binding a highly conserved Phe69.
MeSH term(s)	Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Binding Sites ; Catalysis ; Disulfides/chemistry ; Disulfides/metabolism ; Entropy ; Hydrogen Bonding ; Models, Molecular ; Phylogeny ; Proteobacteria/chemistry ; Proteobacteria/enzymology ; Proteobacteria/genetics ; Proteobacteria/metabolism ; Structure-Activity Relationship ; beta-Lactamases/chemistry ; beta-Lactamases/classification ; beta-Lactamases/genetics ; beta-Lactamases/metabolism
Chemical Substances	Bacterial Proteins ; Disulfides ; beta-Lactamases (EC 3.5.2.6)
Language	English
Publishing date	2011-08-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1466729-0
ISSN	1741-0134 ; 1741-0126
ISSN (online)	1741-0134
ISSN	1741-0126
DOI	10.1093/protein/gzr041
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Article ; Online: Structural basis of activity against aztreonam and extended spectrum cephalosporins for two carbapenem-hydrolyzing class D β-lactamases from Acinetobacter baumannii.

Mitchell, Joshua M / Clasman, Jozlyn R / June, Cynthia M / Kaitany, Kip-Chumba J / LaFleur, James R / Taracila, Magdalena A / Klinger, Neil V / Bonomo, Robert A / Wymore, Troy / Szarecka, Agnieszka / Powers, Rachel A / Leonard, David A

Biochemistry

2015 Volume 54, Issue 10, Page(s) 1976–1987

Abstract: The carbapenem-hydrolyzing class D β-lactamases OXA-23 and OXA-24/40 have emerged worldwide as causative agents for β-lactam antibiotic resistance in Acinetobacter species. Many variants of these enzymes have appeared clinically, including OXA-160 and ... ...

Abstract	The carbapenem-hydrolyzing class D β-lactamases OXA-23 and OXA-24/40 have emerged worldwide as causative agents for β-lactam antibiotic resistance in Acinetobacter species. Many variants of these enzymes have appeared clinically, including OXA-160 and OXA-225, which both contain a P → S substitution at homologous positions in the OXA-24/40 and OXA-23 backgrounds, respectively. We purified OXA-160 and OXA-225 and used steady-state kinetic analysis to compare the substrate profiles of these variants to their parental enzymes, OXA-24/40 and OXA-23. OXA-160 and OXA-225 possess greatly enhanced hydrolytic activities against aztreonam, ceftazidime, cefotaxime, and ceftriaxone when compared to OXA-24/40 and OXA-23. These enhanced activities are the result of much lower Km values, suggesting that the P → S substitution enhances the binding affinity of these drugs. We have determined the structures of the acylated forms of OXA-160 (with ceftazidime and aztreonam) and OXA-225 (ceftazidime). These structures show that the R1 oxyimino side-chain of these drugs occupies a space near the β5-β6 loop and the omega loop of the enzymes. The P → S substitution found in OXA-160 and OXA-225 results in a deviation of the β5-β6 loop, relieving the steric clash with the R1 side-chain carboxypropyl group of aztreonam and ceftazidime. These results reveal worrying trends in the enhancement of substrate spectrum of class D β-lactamases but may also provide a map for β-lactam improvement.
MeSH term(s)	Acinetobacter baumannii/enzymology ; Aztreonam/chemistry ; Bacterial Proteins/chemistry ; Cephalosporins/chemistry ; Hydrolysis ; Kinetics ; Protein Structure, Secondary ; beta-Lactamases/chemistry
Chemical Substances	Bacterial Proteins ; Cephalosporins ; beta-Lactamases (EC 3.5.2.6) ; Aztreonam (G2B4VE5GH8)
Language	English
Publishing date	2015-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi501547k
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In stock of ZB MED Cologne/Königswinter

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Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito