SrasV1, PascalFrancis, Corpus, bibRecord, 000002

Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

Identifieur interne : 000002 ( PascalFrancis/Corpus ); précédent : 000001; suivant : 000003

Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

Auteurs : JIAN LEI ; Jeroen R. Mesters ; Christian Drosten ; Stefan Anemüller ; QINGJUN MA ; Rolf Hilgenfeld

Source :

Antiviral research [ 0166-3542 ] ; 2014.

RBID : Pascal:14-0232435

Descripteurs français

Pascal (Inist)
- Structure cristalline, Papain, Coronavirus, Site actif, Structure doigt zinc, Antiviral, Médicament, Conception, Syndrome respiratoire du Moyen-Orient.

English descriptors

KwdEn :
- Active site, Antiviral, Coronavirus, Crystalline structure, Design, Drug, Middle East respiratory syndrome, Papain, Zinc finger structure.

Abstract

The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL^pro) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL^pro is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL^pro, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL^pro. The unique features observed in the crystal structure of the MERS-CoV PL^pro should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

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C01	`01`		`ENG`	@0 The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL^pro) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL^pro is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL^pro, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL^pro. The unique features observed in the crystal structure of the MERS-CoV PL^pro should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.
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Format Inist (serveur)

NO :	PASCAL 14-0232435 INIST
ET :	Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features
AU :	JIAN LEI; MESTERS (Jeroen R.); DROSTEN (Christian); ANEMÜLLER (Stefan); QINGJUN MA; HILGENFELD (Rolf)
AF :	Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160/23538 Lübeck/Allemagne (1 aut., 2 aut., 4 aut., 5 aut., 6 aut.); Institute of Virology, University of Bonn Medical School/53127 Bonn/Allemagne (3 aut.); German Center for Infection Research (DZIF)/Allemagne (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 6 aut.)
DT :	Publication en série; Niveau analytique
SO :	Antiviral research; ISSN 0166-3542; Coden ARSRDR; Royaume-Uni; Da. 2014; Vol. 109; Pp. 72-82; Bibl. 1 p.1/4
LA :	Anglais
EA :	The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL^pro) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL^pro is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL^pro, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL^pro. The unique features observed in the crystal structure of the MERS-CoV PL^pro should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.
CC :	002B02S05; 002B05C02C
FD :	Structure cristalline; Papain; Coronavirus; Site actif; Structure doigt zinc; Antiviral; Médicament; Conception; Syndrome respiratoire du Moyen-Orient
FG :	Cysteine endopeptidases; Peptidases; Hydrolases; Enzyme; Coronaviridae; Nidovirales; Virus; Pathologie de l'appareil respiratoire; Virose; Infection
ED :	Crystalline structure; Papain; Coronavirus; Active site; Zinc finger structure; Antiviral; Drug; Design; Middle East respiratory syndrome
EG :	Cysteine endopeptidases; Peptidases; Hydrolases; Enzyme; Coronaviridae; Nidovirales; Virus; Respiratory disease; Viral disease; Infection
SD :	Estructura cristalina; Papain; Coronavirus; Lugar activo; Estructura dedo zinc; Antiviral; Medicamento; Diseño
LO :	INIST-18839.354000507680020100
ID :	14-0232435

Links to Exploration step

Pascal:14-0232435

Le document en format XML

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<affiliation><inist:fA14 i1="03"><s1>German Center for Infection Research (DZIF)</s1>
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<series><title level="j" type="main">Antiviral research</title>
<title level="j" type="abbreviated">Antivir. res.</title>
<idno type="ISSN">0166-3542</idno>
<imprint><date when="2014">2014</date>
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<term>Papain</term>
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<front><div type="abstract" xml:lang="en">The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL<sup>pro</sup>
) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL<sup>pro</sup>
 is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL<sup>pro</sup>
, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL<sup>pro</sup>
. The unique features observed in the crystal structure of the MERS-CoV PL<sup>pro</sup>
 should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.</div>
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<fA08 i1="01" i2="1" l="ENG"><s1>Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features</s1>
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 is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL<sup>pro</sup>
, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL<sup>pro</sup>
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<server><NO>PASCAL 14-0232435 INIST</NO>
<ET>Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features</ET>
<AU>JIAN LEI; MESTERS (Jeroen R.); DROSTEN (Christian); ANEMÜLLER (Stefan); QINGJUN MA; HILGENFELD (Rolf)</AU>
<AF>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160/23538 Lübeck/Allemagne (1 aut., 2 aut., 4 aut., 5 aut., 6 aut.); Institute of Virology, University of Bonn Medical School/53127 Bonn/Allemagne (3 aut.); German Center for Infection Research (DZIF)/Allemagne (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 6 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Antiviral research; ISSN 0166-3542; Coden ARSRDR; Royaume-Uni; Da. 2014; Vol. 109; Pp. 72-82; Bibl. 1 p.1/4</SO>
<LA>Anglais</LA>
<EA>The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL<sup>pro</sup>
) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL<sup>pro</sup>
 is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL<sup>pro</sup>
, compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL<sup>pro</sup>
. The unique features observed in the crystal structure of the MERS-CoV PL<sup>pro</sup>
 should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.</EA>
<CC>002B02S05; 002B05C02C</CC>
<FD>Structure cristalline; Papain; Coronavirus; Site actif; Structure doigt zinc; Antiviral; Médicament; Conception; Syndrome respiratoire du Moyen-Orient</FD>
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<ED>Crystalline structure; Papain; Coronavirus; Active site; Zinc finger structure; Antiviral; Drug; Design; Middle East respiratory syndrome</ED>
<EG>Cysteine endopeptidases; Peptidases; Hydrolases; Enzyme; Coronaviridae; Nidovirales; Virus; Respiratory disease; Viral disease; Infection</EG>
<SD>Estructura cristalina; Papain; Coronavirus; Lugar activo; Estructura dedo zinc; Antiviral; Medicamento; Diseño</SD>
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Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

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