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  1. Article ; Online: Structural characterization of PaaX, the main repressor of the phenylacetate degradation pathway in Escherichia coli W: A novel fold of transcription regulator proteins.

    Hernández-Rocamora, Víctor M / Molina, Rafael / Alba, Alejandra / Carrasco-López, César / Rojas-Altuve, Alzoray / Panjikar, Santosh / Medina, Ana / Usón, Isabel / Alfonso, Carlos / Galán, Beatriz / Rivas, Germán / Hermoso, Juan A / Sanz, Jesús M

    International journal of biological macromolecules

    2023  Volume 254, Issue Pt 3, Page(s) 127935

    Abstract: PaaX is a transcriptional repressor of the phenylacetic acid (PAA) catabolic pathway, a central route for bacterial aerobic degradation of aromatic compounds. Induction of the route is achieved through the release of PaaX from its promoter sequences by ... ...

    Abstract PaaX is a transcriptional repressor of the phenylacetic acid (PAA) catabolic pathway, a central route for bacterial aerobic degradation of aromatic compounds. Induction of the route is achieved through the release of PaaX from its promoter sequences by the first compound of the pathway, phenylacetyl-coenzyme A (PA-CoA). We report the crystal structure of PaaX from Escherichia coli W. PaaX displays a novel type of fold for transcription regulators, showing a dimeric conformation where the monomers present a three-domain structure: an N-terminal winged helix-turn-helix domain, a dimerization domain similar to the Cas2 protein and a C-terminal domain without structural homologs. The domains are separated by a crevice amenable to harbour a PA-CoA molecule. The biophysical characterization of the protein in solution confirmed several hints predicted from the structure, i.e. its dimeric conformation, a modest importance of cysteines and a high dependence of solubility and thermostability on ionic strength. At a moderately acidic pH, the protein formed a stable folding intermediate with remaining α-helical structure, a disrupted tertiary structure and exposed hydrophobic patches. Our results provide valuable information to understand the stability and mechanism of PaaX and pave the way for further analysis of other regulators with similar structural configurations.
    MeSH term(s) Escherichia coli/metabolism ; Repressor Proteins/metabolism ; Promoter Regions, Genetic ; Phenylacetates ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism
    Chemical Substances phenylacetic acid (ER5I1W795A) ; Repressor Proteins ; Phenylacetates ; Bacterial Proteins ; Escherichia coli Proteins
    Language English
    Publishing date 2023-11-09
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2023.127935
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  2. Article: Binding of non-canonical peptidoglycan controls

    Espaillat, Akbar / Carrasco-López, Cesar / Bernardo-García, Noelia / Rojas-Altuve, Alzoray / Klett, Javier / Morreale, Antonio / Hermoso, Juan A / Cava, Felipe

    Computational and structural biotechnology journal

    2021  Volume 19, Page(s) 1119–1126

    Abstract: Broad-spectrum amino acid racemases (Bsrs) enable bacteria to generate non-canonical D-amino acids (NCDAAs), whose roles and impact on microbial physiology, including modulation of cell wall structure and dissolution of biofilms, are just beginning to be ...

    Abstract Broad-spectrum amino acid racemases (Bsrs) enable bacteria to generate non-canonical D-amino acids (NCDAAs), whose roles and impact on microbial physiology, including modulation of cell wall structure and dissolution of biofilms, are just beginning to be appreciated. Here we used a diverse array of structural, biochemical and molecular simulation studies to define and characterize how BsrV is post-translationally regulated. We discovered that contrary to
    Language English
    Publishing date 2021-01-26
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2001-0370
    ISSN 2001-0370
    DOI 10.1016/j.csbj.2021.01.031
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  3. Article ; Online: Disruption of allosteric response as an unprecedented mechanism of resistance to antibiotics.

    Fishovitz, Jennifer / Rojas-Altuve, Alzoray / Otero, Lisandro H / Dawley, Matthew / Carrasco-López, Cesar / Chang, Mayland / Hermoso, Juan A / Mobashery, Shahriar

    Journal of the American Chemical Society

    2014  Volume 136, Issue 28, Page(s) 9814–9817

    Abstract: Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads ... ...

    Abstract Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.
    MeSH term(s) Anti-Bacterial Agents/pharmacology ; Cephalosporins/pharmacology ; Drug Resistance, Bacterial/drug effects ; Drug Resistance, Bacterial/physiology ; Methicillin-Resistant Staphylococcus aureus/drug effects ; Methicillin-Resistant Staphylococcus aureus/genetics ; Models, Molecular ; Molecular Conformation ; Mutation/physiology ; Penicillin-Binding Proteins/chemistry ; Penicillin-Binding Proteins/drug effects ; Penicillin-Binding Proteins/genetics ; Protein Conformation ; X-Ray Diffraction ; Ceftaroline
    Chemical Substances Anti-Bacterial Agents ; Cephalosporins ; Penicillin-Binding Proteins
    Language English
    Publishing date 2014-07-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/ja5030657
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics

    Fishovitz, Jennifer / Rojas-Altuve, Alzoray / Otero, LisandroH / Dawley, Matthew / Carrasco-López, Cesar / Chang, Mayland / Hermoso, Juan A / Mobashery, Shahriar

    Journal of the American Chemical Society. 2014 July 16, v. 136, no. 28

    2014  

    Abstract: Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads ... ...

    Abstract Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.
    Keywords X-radiation ; active sites ; antibiotic resistance ; biosynthesis ; death ; methicillin ; methicillin-resistant Staphylococcus aureus ; mutants
    Language English
    Dates of publication 2014-0716
    Size p. 9814-9817.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021%2Fja5030657
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Crystallization and preliminary X-ray diffraction studies of the transcriptional repressor PaaX, the main regulator of the phenylacetic acid degradation pathway in Escherichia coli W.

    Rojas-Altuve, Alzoray / Carrasco-López, César / Hernández-Rocamora, Víctor M / Sanz, Jesús M / Hermoso, Juan A

    Acta crystallographica. Section F, Structural biology and crystallization communications

    2011  Volume 67, Issue Pt 10, Page(s) 1278–1280

    Abstract: PaaX is the main regulator of the phenylacetic acid aerobic degradation pathway in bacteria and acts as a transcriptional repressor in the absence of its inducer phenylacetyl-coenzyme A. The natural presence and the recent accumulation of a variety of ... ...

    Abstract PaaX is the main regulator of the phenylacetic acid aerobic degradation pathway in bacteria and acts as a transcriptional repressor in the absence of its inducer phenylacetyl-coenzyme A. The natural presence and the recent accumulation of a variety of highly toxic aromatic compounds owing to human pollution has created considerable interest in the study of degradation pathways in bacteria, the most important microorganisms capable of recycling these compounds, in order to design and apply novel bioremediation strategies. PaaX from Escherichia coli W was cloned, overexpressed, purified and crystallized using the sitting-drop vapour-diffusion method at 291 K. Crystals grew from a mixture of 0.9 M Li(2)SO(4) and 0.5 M sodium citrate pH 5.8. These crystals, which belonged to the monoclinic space group C2 with unit-cell parameters a = 167.88, b = 106.23, c = 85.87 Å, β = 108.33°, allowed the collection of an X-ray data set to 2.3 Å resolution.
    MeSH term(s) Crystallization ; Crystallography, X-Ray ; Escherichia coli/chemistry ; Escherichia coli Proteins/chemistry ; Repressor Proteins/chemistry
    Chemical Substances Escherichia coli Proteins ; PaaX protein, E coli ; Repressor Proteins
    Language English
    Publishing date 2011-09-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1744-3091
    ISSN (online) 1744-3091
    DOI 10.1107/S1744309111029873
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  6. Article ; Online: Crystal structures of bacterial peptidoglycan amidase AmpD and an unprecedented activation mechanism.

    Carrasco-López, Cesar / Rojas-Altuve, Alzoray / Zhang, Weilie / Hesek, Dusan / Lee, Mijoon / Barbe, Sophie / André, Isabelle / Ferrer, Pilar / Silva-Martin, Noella / Castro, German R / Martínez-Ripoll, Martín / Mobashery, Shahriar / Hermoso, Juan A

    The Journal of biological chemistry

    2011  Volume 286, Issue 36, Page(s) 31714–31722

    Abstract: AmpD is a cytoplasmic peptidoglycan (PG) amidase involved in bacterial cell-wall recycling and in induction of β-lactamase, a key enzyme of β-lactam antibiotic resistance. AmpD belongs to the amidase_2 family that includes zinc-dependent amidases and the ...

    Abstract AmpD is a cytoplasmic peptidoglycan (PG) amidase involved in bacterial cell-wall recycling and in induction of β-lactamase, a key enzyme of β-lactam antibiotic resistance. AmpD belongs to the amidase_2 family that includes zinc-dependent amidases and the peptidoglycan-recognition proteins (PGRPs), highly conserved pattern-recognition molecules of the immune system. Crystal structures of Citrobacter freundii AmpD were solved in this study for the apoenzyme, for the holoenzyme at two different pH values, and for the complex with the reaction products, providing insights into the PG recognition and the catalytic process. These structures are significantly different compared with the previously reported NMR structure for the same protein. The NMR structure does not possess an accessible active site and shows the protein in what is proposed herein as an inactive "closed" conformation. The transition of the protein from this inactive conformation to the active "open" conformation, as seen in the x-ray structures, was studied by targeted molecular dynamics simulations, which revealed large conformational rearrangements (as much as 17 Å) in four specific regions representing one-third of the entire protein. It is proposed that the large conformational change that would take the inactive NMR structure to the active x-ray structure represents an unprecedented mechanism for activation of AmpD. Analysis is presented to argue that this activation mechanism might be representative of a regulatory process for other intracellular members of the bacterial amidase_2 family of enzymes.
    MeSH term(s) Amidohydrolases/chemistry ; Bacterial Proteins/chemistry ; Catalysis ; Citrobacter freundii/enzymology ; Crystallography, X-Ray ; Enzyme Activation ; Hydrogen-Ion Concentration ; N-Acetylmuramoyl-L-alanine Amidase/chemistry ; Peptidoglycan/metabolism ; Protein Structure, Tertiary ; Substrate Specificity
    Chemical Substances Bacterial Proteins ; Peptidoglycan ; Amidohydrolases (EC 3.5.-) ; N-Acetylmuramoyl-L-alanine Amidase (EC 3.5.1.28)
    Language English
    Publishing date 2011-07-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M111.264366
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  7. Article ; Online: How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function.

    Otero, Lisandro H / Rojas-Altuve, Alzoray / Llarrull, Leticia I / Carrasco-López, Cesar / Kumarasiri, Malika / Lastochkin, Elena / Fishovitz, Jennifer / Dawley, Matthew / Hesek, Dusan / Lee, Mijoon / Johnson, Jarrod W / Fisher, Jed F / Chang, Mayland / Mobashery, Shahriar / Hermoso, Juan A

    Proceedings of the National Academy of Sciences of the United States of America

    2013  Volume 110, Issue 42, Page(s) 16808–16813

    Abstract: The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The high-molecular mass penicillin binding proteins of bacteria ... ...

    Abstract The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The high-molecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that comprises the bacterial cell wall. In bacteria susceptible to β-lactam antibiotics, the transpeptidase activity of their penicillin binding proteins (PBPs) is lost as a result of irreversible acylation of an active site serine by the β-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to β-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with β-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain--a remarkable 60 Å distant from the DD-transpeptidase active site--discovered by crystallographic analysis of a soluble construct of PBP2a. When this allosteric site is occupied, a multiresidue conformational change culminates in the opening of the active site to permit substrate entry. This same crystallographic analysis also reveals the identity of three allosteric ligands: muramic acid (a saccharide component of the peptidoglycan), the cell wall peptidoglycan, and ceftaroline, a recently approved anti-MRSA β-lactam antibiotic. The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second β-lactam molecule, opens an unprecedented realm for β-lactam antibiotic structure-based design.
    MeSH term(s) Acylation/physiology ; Allosteric Regulation/physiology ; Catalytic Domain ; Cephalosporins/chemistry ; Cephalosporins/metabolism ; Crystallography, X-Ray ; Methicillin Resistance/physiology ; Methicillin-Resistant Staphylococcus aureus/enzymology ; Methicillin-Resistant Staphylococcus aureus/genetics ; Muramic Acids/chemistry ; Muramic Acids/metabolism ; Penicillin-Binding Proteins/chemistry ; Penicillin-Binding Proteins/genetics ; Penicillin-Binding Proteins/metabolism ; Peptidoglycan/chemistry ; Peptidoglycan/metabolism ; Substrate Specificity/physiology ; Ceftaroline
    Chemical Substances Cephalosporins ; Muramic Acids ; Penicillin-Binding Proteins ; Peptidoglycan
    Language English
    Publishing date 2013-10-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1300118110
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