scholarly journals Structural and functional studies of Spr1654: an essential aminotransferase in teichoic acid biosynthesis in Streptococcus pneumoniae

Open Biology ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 170248
Author(s):  
Xiao Han ◽  
Renhua Sun ◽  
Tatyana Sandalova ◽  
Adnane Achour
Keyword(s):  
Streptococcus Pneumoniae ◽  
Crystal Structures ◽  
Rational Design ◽  
Teichoic Acid ◽  
Amino Sugar ◽  
Acid Biosynthesis ◽  
Functional Studies ◽  
Structural Superposition ◽  
Amino Donor ◽  
Therapeutic Compounds

Spr1654 from Streptococcus pneumoniae plays a key role in the production of unusual sugars, presumably functioning as a pyridoxal-5′-phosphate (PLP)-dependent aminotransferase. Spr1654 was predicted to catalyse the transferring of amino group to form the amino sugar 2-acetamido-4-amino-2, 4, 6-trideoxygalactose moiety (AATGal), representing a crucial step in biosynthesis of teichoic acids in S. pneumoniae . We have determined the crystal structures of the apo-, PLP- and PMP-bound forms of Spr1654. Spr1654 forms a homodimer, in which each monomer contains one active site. Using spectrophotometry and based on absorbance profiles of PLP- and PMP-formed enzymes, our results indicate that l -glutamate is most likely the preferred amino donor. Structural superposition of the crystal structures of Spr1654 on previously determined structures of other sugar aminotransferases in complex with glutamate and/or UDP-activated sugar allowed us to identify key Spr1654 residues for ligand binding and catalysis. The crystal structures of Spr1654 and in complex with PLP and PMP can direct the future rational design of novel therapeutic compounds against S. pneumoniae .

Crystal Structures of the Human and Fungal Cytosolic Leucyl-tRNA Synthetase Editing Domains: A Structural Basis for the Rational Design of Antifungal Benzoxaboroles

2009 ◽  
Vol 390 (2) ◽  
pp. 196-207 ◽  
Author(s):  
Elena Seiradake ◽  
Weimin Mao ◽  
Vincent Hernandez ◽  
Stephen J. Baker ◽  
Jacob J. Plattner ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Rational Design ◽  
Trna Synthetase ◽  
Structural Basis

scholarly journals Hidden Mode of Action of Glycopeptide Antibiotics: Inhibition of Wall Teichoic Acid Biosynthesis

2017 ◽  
Vol 121 (16) ◽  
pp. 3925-3932 ◽  
Author(s):  
Manmilan Singh ◽  
James Chang ◽  
Lauryn Coffman ◽  
Sung Joon Kim
Keyword(s):  
Mode Of Action ◽  
Teichoic Acid ◽  
Glycopeptide Antibiotics ◽  
Acid Biosynthesis ◽  
Wall Teichoic Acid

Crystal Structures of Dimethoxyanthracens: A Clue to a Rational Design of Packing Structures of π‐Conjugated Molecules

2020 ◽  
Vol 15 (6) ◽  
pp. 915-919 ◽  
Author(s):  
Kazuo Takimiya ◽  
Takuya Ogaki ◽  
Chengyuan Wang ◽  
Kohsuke Kawabata
Keyword(s):  
Crystal Structures ◽  
Rational Design ◽  
Conjugated Molecules

Crystal structure of nickel manganese-layered double hydroxide@cobaltosic oxides on nickel foam towards high-performance supercapacitors

CrystEngComm ◽  
2019 ◽  
Vol 21 (3) ◽  
pp. 470-477 ◽  
Author(s):  
Huihua Peng ◽  
Chuan Jing ◽  
Jie Chen ◽  
Deyi Jiang ◽  
Xiaoying Liu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Layered Double Hydroxide ◽  
High Performance ◽  
Rational Design ◽  
Electrode Materials ◽  
Nickel Foam ◽  
Double Hydroxide ◽  
Nickel Manganese

Rational design of the crystal structures of electrode materials is considered as an important strategy to construct high-performance supercapacitors.

scholarly journals A Choline-Recognizing Monomeric Lysin, ClyJ-3m, Shows Elevated Activity against Streptococcus pneumoniae

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Dehua Luo ◽  
Li Huang ◽  
Vijay Singh Gondil ◽  
Wanli Zhou ◽  
Wan Yang ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Bactericidal Activity ◽  
Rational Design ◽  
Biochemical Characterization ◽  
Catalytic Domain ◽  
Intraperitoneal Administration ◽  
Pharmacokinetic Analysis ◽  
Content Type ◽  
Equal Dose ◽  
Elevated Activity

ABSTRACT Streptococcus pneumoniae is a leading pathogen for bacterial pneumonia, which can be treated with bacteriophage lysins harboring a conserved choline binding module (CBM). Such lysins regularly function as choline-recognizing dimers. Previously, we reported a pneumococcus-specific lysin ClyJ comprising the binding domain from the putative endolysin gp20 from the Streptococcus phage SPSL1 and the CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) catalytic domain from the PlyC lysin. A variant of ClyJ with a shortened linker, i.e., ClyJ-3, shows improved activity and reduced cytotoxicity. Resembling typical CBM-containing lysins, ClyJ-3 dimerized upon binding with choline. Herein, we further report a choline-recognizing variant of ClyJ-3, i.e., ClyJ-3m, constructed by deleting its C-terminal tail. Biochemical characterization showed that ClyJ-3m remains a monomer after it binds to choline yet exhibits improved bactericidal activity against multiple pneumococcal strains with different serotypes. In an S. pneumoniae-infected bacteremia model, a single intraperitoneal administration of 2.32 μg/mouse of ClyJ-3m showed 70% protection, while only 20% of mice survived in the group receiving an equal dose of ClyJ-3 (P < 0.05). A pharmacokinetic analysis following single intravenously doses of 0.29 and 1.16 mg/kg of ClyJ-3 or ClyJ-3m in BALB/c mice revealed that ClyJ-3m shows a similar half-life but less clearance and a greater area under curve than ClyJ-3. Taken together, the choline-recognizing monomer ClyJ-3m exhibited enhanced bactericidal activity and improved pharmacokinetic proprieties compared to those of its parental ClyJ-3 lysin. Our study also provides a new way for rational design and programmed engineering of lysins targeting S. pneumoniae.

scholarly journals Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Li Chen ◽  
Wen-Tao Hou ◽  
Tao Fan ◽  
Banghui Liu ◽  
Ting Pan ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Rational Design ◽  
Teichoic Acid ◽  
Inhibitory Mechanism ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Design And Optimization ◽  
Cryo Electron Microscopy

ABSTRACT The wall teichoic acid (WTA) is a major cell wall component of Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), a common cause of fatal clinical infections in humans. Thus, the indispensable ABC transporter TarGH, which flips WTA from cytoplasm to extracellular space, becomes a promising target of anti-MRSA drugs. Here, we report the 3.9-Å cryo-electron microscopy (cryo-EM) structure of a 50% sequence-identical homolog of TarGH from Alicyclobacillus herbarius at an ATP-free and inward-facing conformation. Structural analysis combined with activity assays enables us to clearly decode the binding site and inhibitory mechanism of the anti-MRSA inhibitor Targocil, which targets TarGH. Moreover, we propose a “crankshaft conrod” mechanism utilized by TarGH, which can be applied to similar ABC transporters that translocate a rather big substrate through relatively subtle conformational changes. These findings provide a structural basis for the rational design and optimization of antibiotics against MRSA. IMPORTANCE The wall teichoic acid (WTA) is a major component of cell wall and a pathogenic factor in methicillin-resistant Staphylococcus aureus (MRSA). The ABC transporter TarGH is indispensable for flipping WTA precursor from cytoplasm to the extracellular space, thus making it a promising drug target for anti-MRSA agents. The 3.9-Å cryo-EM structure of a TarGH homolog helps us to decode the binding site and inhibitory mechanism of a recently reported inhibitor, Targocil, and provides a structural platform for rational design and optimization of potential antibiotics. Moreover, we propose a “crankshaft conrod” mechanism to explain how a big substrate is translocated through subtle conformational changes of type II exporters. These findings advance our understanding of anti-MRSA drug design and ABC transporters.

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