2. Luria-bertani and . Media, Protein expression was induced by the addition of 0.5 mM IPTG (isopropyl--D-thiogalactopyranoside) After overnight incubation at 17°C, cells expressing nsp10, nsp16, or a mixture of nsp10 and nsp16 (in equal volumes) were pelleted by centrifugation (13,000 g, 10 min) and frozen before resuspension in lysis buffer (50 mM HEPES [pH 7.5], 300 mM NaCl, 30 mM imidazole, 10% glycerol supplemented with 1 mM phenylmethylsulfonyl fluoride, 0.25 mg/ml lysozyme, 10 g/ml DNase I) After sonication and clarification (80,000 g, 4°C, 30 min), the supernatants were incubated with HisPur cobalt resin (Thermo Scientific) at 4°C with gentle shaking for 30 min, After washing in buffer W [50 mM HEPES (pH 7.5), 40 mM imidazole, 10% glycerol, and 1 mM Tris(2-carboxyethyl)phosphine hydrochloride (TCEP-HCl)] containing 300 or 500 mM NaCl

E. De-wit, N. Van-doremalen, D. Falzarano, and V. Munster, SARS and MERS: recent insights into emerging coronaviruses, Nature Reviews Microbiology, vol.113, issue.8, pp.523-534, 2016.
DOI : 10.1073/pnas.1517719113

Y. Arabi, A. Harthi, J. Hussein, A. Bouchama, S. Johani et al., Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV), Infection, vol.209, issue.12, pp.495-501, 2015.
DOI : 10.1093/infdis/jiu068

URL : https://link.springer.com/content/pdf/10.1007%2Fs15010-015-0720-y.pdf

J. Chan, S. Lau, K. To, V. Cheng, P. Woo et al., Middle East Respiratory Syndrome Coronavirus: Another Zoonotic Betacoronavirus Causing SARS-Like Disease, Clinical Microbiology Reviews, vol.28, issue.2, pp.465-52200102, 2015.
DOI : 10.1128/CMR.00102-14

URL : http://cmr.asm.org/content/28/2/465.full.pdf

P. Durai, M. Batool, M. Shah, and S. Choi, Middle East respiratory syndrome coronavirus: transmission, virology and therapeutic targeting to aid in outbreak control, Experimental & Molecular Medicine, vol.5, issue.8, p.181, 2015.
DOI : 10.3201/eid2002.131182

URL : http://www.nature.com/emm/journal/v47/n8/pdf/emm201576a.pdf

C. Reusken, E. Farag, M. Jonges, G. Godeke, A. Sayed et al., Middle East respiratory syndrome coronavirus (MERS-CoV) RNA and neutralising antibodies in milk collected according to local customs from dromedary camels, Euro Surveill, vol.19, pp.1-5, 2014.
DOI : 10.2807/1560-7917.es2014.19.23.20829

URL : http://www.ecdc.europa.eu/en/publications/Publications/RRA-Middle-East-respiratory-syndrome-coronavirus-update10.pdf

V. Raj, A. Osterhaus, R. Fouchier, and B. Haagmans, MERS: emergence of a novel human coronavirus, Current Opinion in Virology, vol.5, pp.58-62, 2014.
DOI : 10.1016/j.coviro.2014.01.010

URL : http://europepmc.org/articles/pmc4028407?pdf=render

A. Fehr, R. Channappanavar, and S. Perlman, Middle East Respiratory Syndrome: Emergence of a Pathogenic Human Coronavirus, Annual Review of Medicine, vol.68, issue.1, pp.51215-031152, 2016.
DOI : 10.1146/annurev-med-051215-031152

URL : http://europepmc.org/articles/pmc5353356?pdf=render

J. Sabir, T. Lam, M. Ahmed, L. Li, Y. Shen et al., Co-circulation of three camel coronavirus species and recombination of MERS-CoVs in Saudi Arabia, Science, vol.60, issue.3, pp.81-84, 2016.
DOI : 10.1093/cid/ciu812

N. Van-doremalen, T. Bushmaker, and V. Munster, Stability of Middle East respiratory syndrome coronavirus (MERS-CoV) under different environmental conditions, Eurosurveillance, vol.18, issue.38, pp.1-4, 2013.
DOI : 10.1155/2011/734690

V. Raj, H. Mou, S. Smits, D. Dekkers, M. Müller et al., Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC, Nature, vol.3, issue.7440, pp.251-254, 2013.
DOI : 10.1016/j.stem.2010.02.014

S. Van-boheemen, D. Graaf, M. Lauber, C. Bestebroer, T. Raj et al., Genomic Characterization of a Newly Discovered Coronavirus Associated with Acute Respiratory Distress Syndrome in Humans, mBio, vol.3, issue.6, pp.473-485, 2012.
DOI : 10.1128/mBio.00473-12

J. Ziebuhr, E. Snijder, and A. Gorbalenya, Virus-encoded proteinases and proteolytic processing in the Nidovirales, Journal of General Virology, vol.440, issue.4, pp.853-8790022, 2000.
DOI : 10.1007/978-1-4615-1899-0_70

URL : http://jgv.microbiologyresearch.org/deliver/fulltext/jgv/81/4/0853.pdf?itemId=/content/journal/jgv/10.1099/0022-1317-81-4-853&mimeType=pdf&isFastTrackArticle=

N. Cougot, E. Van-dijk, S. Babajko, and B. Séraphin, ???Cap-tabolism???, Trends in Biochemical Sciences, vol.29, issue.8, pp.436-444, 2004.
DOI : 10.1016/j.tibs.2004.06.008

E. Bouveret, G. Rigaut, A. Shevchenko, M. Wilm, and B. Séraphin, A Sm-like protein complex that participates in mRNA degradation, The EMBO Journal, vol.19, issue.7, pp.1661-1671, 2000.
DOI : 10.1093/emboj/19.7.1661

URL : http://emboj.embopress.org/content/embojnl/19/7/1661.full.pdf

R. Züst, L. Cervantes-barragan, M. Habjan, R. Maier, B. Neuman et al., Ribose 2???-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5, Nature Immunology, vol.454, issue.2, pp.137-143, 2011.
DOI : 10.1128/JVI.76.8.3697-3708.2002

C. Schuberth-wagner, J. Ludwig, A. Bruder, A. Herzner, T. Zillinger et al., A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2???O-Methylated Self RNA, Immunity, vol.43, issue.1, pp.41-51, 2015.
DOI : 10.1016/j.immuni.2015.06.015

S. Devarkar, C. Wang, M. Miller, A. Ramanathan, F. Jiang et al., Structural basis for m7G recognition and 2???-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I, Proceedings of the National Academy of Sciences, vol.2, issue.2, pp.596-601
DOI : 10.1038/nm.1887

URL : http://www.pnas.org/content/113/3/596.full.pdf

J. Hyde and M. Diamond, Innate immune restriction and antagonism of viral RNA lacking 2??-O methylation, Virology, vol.479, issue.480, pp.479-48066, 2015.
DOI : 10.1016/j.virol.2015.01.019

URL : https://doi.org/10.1016/j.virol.2015.01.019

E. Decroly, F. Ferron, J. Lescar, and B. Canard, Conventional and unconventional mechanisms for capping viral mRNA, Nature Reviews Microbiology, vol.1, issue.1, pp.51-65, 2012.
DOI : 10.1016/j.tibs.2007.05.001

M. Diamond, IFIT1: A dual sensor and effector molecule that detects non-2???-O methylated viral RNA and inhibits its translation, Cytokine & Growth Factor Reviews, vol.25, issue.5, pp.543-550, 2014.
DOI : 10.1016/j.cytogfr.2014.05.002

URL : http://europepmc.org/articles/pmc4234691?pdf=render

M. Daugherty, A. Schaller, A. Geballe, and H. Malik, Author response, eLife, vol.12, issue.480, pp.1-22, 2016.
DOI : 10.7554/eLife.14228.023

K. Ivanov and J. Ziebuhr, Human Coronavirus 229E Nonstructural Protein 13: Characterization of Duplex-Unwinding, Nucleoside Triphosphatase, and RNA 5'-Triphosphatase Activities, Journal of Virology, vol.78, issue.14, pp.7833-7838, 2004.
DOI : 10.1128/JVI.78.14.7833-7838.2004

URL : http://jvi.asm.org/content/78/14/7833.full.pdf

Y. Chen, H. Cai, J. Pan, N. Xiang, P. Tien et al., Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase, Proceedings of the National Academy of Sciences, vol.32, issue.1, pp.3484-3489, 2009.
DOI : 10.1093/nar/gnh007

URL : http://www.pnas.org/content/106/9/3484.full.pdf

M. Bouvet, C. Debarnot, I. Imbert, B. Selisko, E. Snijder et al., In Vitro Reconstitution of SARS-Coronavirus mRNA Cap Methylation, PLoS Pathogens, vol.235, issue.4, p.1000863, 2010.
DOI : 10.1371/journal.ppat.1000863.s002

URL : https://doi.org/10.1371/journal.ppat.1000863

Y. Chen, C. Su, M. Ke, J. X. Xu, L. Zhang et al., Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2???-O-Methylation by nsp16/nsp10 Protein Complex, PLoS Pathogens, vol.71, issue.10, p.1002294, 2011.
DOI : 10.1371/journal.ppat.1002294.s005

URL : https://doi.org/10.1371/journal.ppat.1002294

M. Bouvet, A. Lugari, C. Posthuma, J. Zevenhoven, S. Bernard et al., Nsp10, a Critical Co-factor for Activation of Multiple Replicative Enzymes, Journal of Biological Chemistry, vol.73, issue.37, pp.25783-25796, 2014.
DOI : 10.1093/bioinformatics/15.4.305

M. Von-grotthuss, L. Wyrwicz, and L. Rychlewski, mRNA Cap-1 Methyltransferase in the SARS Genome, Cell, vol.113, issue.6, pp.701-702, 2003.
DOI : 10.1016/S0092-8674(03)00424-0

E. Decroly, I. Imbert, B. Coutard, M. Bouvet, B. Selisko et al., Coronavirus Nonstructural Protein 16 Is a Cap-0 Binding Enzyme Possessing (Nucleoside-2'O)-Methyltransferase Activity, Journal of Virology, vol.82, issue.16, pp.8071-808400407, 2008.
DOI : 10.1128/JVI.00407-08

URL : http://jvi.asm.org/content/82/16/8071.full.pdf

E. Decroly, C. Debarnot, F. Ferron, M. Bouvet, B. Coutard et al., Crystal Structure and Functional Analysis of the SARS-Coronavirus RNA Cap 2???-O-Methyltransferase nsp10/nsp16 Complex, PLoS Pathogens, vol.35, issue.5, p.1002059, 2011.
DOI : 10.1371/journal.ppat.1002059.s006

URL : https://doi.org/10.1371/journal.ppat.1002059

A. Lugari, S. Betzi, E. Decroly, E. Bonnaud, A. Hermant et al., -Methyltransferase Activation Interface between Severe Acute Respiratory Syndrome Coronavirus nsp10 and nsp16, Journal of Biological Chemistry, vol.1, issue.43, pp.33230-33241, 2010.
DOI : 10.1093/bioinformatics/15.4.305

URL : http://www.jbc.org/content/285/43/33230.full.pdf

J. Martin and F. Mcmillan, SAM (dependent) I AM: the S-adenosylmethionine-dependent methyltransferase fold, Current Opinion in Structural Biology, vol.12, issue.6, pp.783-793, 2002.
DOI : 10.1016/S0959-440X(02)00391-3

Y. Wang, Y. Sun, A. Wu, S. Xu, R. Pan et al., ABSTRACT, Journal of Virology, vol.89, issue.16, pp.8416-842700948, 2015.
DOI : 10.1128/JVI.00948-15

URL : https://hal.archives-ouvertes.fr/hal-01351397

V. Menachery, . Jr, L. Bly-josset, L. Gralinski, T. Scobey et al., Attenuation and Restoration of Severe Acute Respiratory Syndrome Coronavirus Mutant Lacking 2'-O-Methyltransferase Activity, Journal of Virology, vol.88, issue.8, pp.4251-4264, 2014.
DOI : 10.1128/JVI.03571-13

URL : http://jvi.asm.org/content/88/8/4251.full.pdf

R. Züst, H. Dong, X. Li, D. Chang, B. Zhang et al., Rational Design of a Live Attenuated Dengue Vaccine: 2???-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques, PLoS Pathogens, vol.25, issue.2, p.1003521, 2013.
DOI : 10.1371/journal.ppat.1003521.s007

J. Finkelstein, Methionine metabolism in mammals, J Nutr Biochem, vol.23, pp.228-237, 1990.
DOI : 10.1016/0003-9861(67)90162-2

M. Svardal and M. Uelands, Compartmentalization of S-adenosylhomocysteine in rat liver, J Biol Chem, vol.262, pp.15413-15417, 1987.

F. Ferron, E. Decroly, B. Selisko, and B. Canard, The viral RNA capping machinery as a target for antiviral drugs, Antiviral Research, vol.96, issue.1, pp.21-31, 2012.
DOI : 10.1016/j.antiviral.2012.07.007

V. Luzhkov, B. Selisko, A. Nordqvist, F. Peyrane, E. Decroly et al., Virtual screening and bioassay study of novel inhibitors for dengue virus mRNA cap (nucleoside-2???O)-methyltransferase, Bioorganic & Medicinal Chemistry, vol.15, issue.24, pp.7795-7802, 2007.
DOI : 10.1016/j.bmc.2007.08.049

H. Dong, D. Chang, M. Hua, S. Lim, Y. Chionh et al., 2???-O Methylation of Internal Adenosine by Flavivirus NS5 Methyltransferase, PLoS Pathogens, vol.286, issue.4, 2012.
DOI : 10.1371/journal.ppat.1002642.g007

X. Mao and S. Shuman, Intrinsic RNA (guanine-7) methyltransferase activity of the vaccinia virus capping enzyme D1 subunit is stimulated by the D12 subunit, J Biol Chem, vol.269, pp.24472-24479, 1994.

M. De-la-peña, O. Kyrieleis, and S. Cusack, Structural insights into the mechanism and evolution of the vaccinia virus mRNA cap N7 methyl-transferase, The EMBO Journal, vol.81, issue.23, pp.4913-4925, 2007.
DOI : 10.1038/sj.emboj.7601912

D. Varshney, A. Petit, J. Bueren-calabuig, C. Jansen, D. Fletcher et al., Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM, Nucleic Acids Research, vol.287, issue.21, pp.10423-10436, 2016.
DOI : 10.1006/viro.2001.1006

URL : https://academic.oup.com/nar/article-pdf/44/21/10423/9598479/gkw637.pdf

A. Hodel, P. Gershon, and F. Quiocho, Structural Basis for Sequence-Nonspecific Recognition of 5???-Capped mRNA by a Cap-Modifying Enzyme, Molecular Cell, vol.1, issue.3, pp.443-447, 1998.
DOI : 10.1016/S1097-2765(00)80044-1

URL : https://doi.org/10.1016/s1097-2765(00)80044-1

D. Clercq and E. , S-adenosylhomocysteine hydrolase inhibitors as broad-spectrum antiviral agents, Biochemical Pharmacology, vol.36, issue.16, pp.2567-2575, 1987.
DOI : 10.1016/0006-2952(87)90533-8

D. Clercq and E. , Molecular targets for antiviral agents, J Pharmacol Exp Ther, vol.297, pp.1-10, 2001.

M. Bray, J. Raymond, T. Geisbert, and R. Baker, 3-Deazaneplanocin A induces massively increased interferon-?? production in Ebola virus-infected mice, Antiviral Research, vol.55, issue.1, pp.151-159, 2002.
DOI : 10.1016/S0166-3542(02)00018-9

URL : https://zenodo.org/record/1259873/files/article.pdf

D. Clercq and E. , Strategies in the design of antiviral drugs, Nature Reviews Drug Discovery, vol.45, issue.Suppl. 1, pp.13-25, 2002.
DOI : 10.1016/S0166-3542(00)00066-8

M. Habjan, P. Hubel, L. Lacerda, C. Benda, C. Holze et al., Sequestration by IFIT1 Impairs Translation of 2???O-unmethylated Capped RNA, PLoS Pathogens, vol.253, issue.10, p.1003663, 2013.
DOI : 10.1371/journal.ppat.1003663.s009

URL : https://doi.org/10.1371/journal.ppat.1003663

T. Lavergne, J. Bertrand, J. Vasseur, and F. Debart, A Base-Labile Group for 2???-OH Protection of Ribonucleosides: A Major Challenge for RNA Synthesis, Chemistry - A European Journal, vol.11, issue.30, 2008.
DOI : 10.1002/chem.200801392

URL : https://hal.archives-ouvertes.fr/hal-00346580

I. Zlatev, T. Lavergne, F. Debart, J. Vasseur, M. Manoharan et al., Efficient Solid-Phase Chemical Synthesis of 5???-Triphosphates of DNA, RNA, and their Analogues, Organic Letters, vol.12, issue.10, pp.2190-2193, 2010.
DOI : 10.1021/ol1004214

URL : https://hal.archives-ouvertes.fr/hal-00519477

Y. Thillier, E. Decroly, F. Morvan, B. Canard, J. Vasseur et al., Synthesis of 5' cap-0 and cap-1 RNAs using solid-phase chemistry coupled with enzymatic methylation by human (guanine-N7)-methyl transferase, RNA, vol.18, issue.4, pp.856-868, 2012.
DOI : 10.1261/rna.030932.111

URL : https://hal.archives-ouvertes.fr/hal-00700861

A. Shatkin, Capping of eucaryotic mRNAs, Cell, vol.9, issue.4, pp.645-6530092, 1016.
DOI : 10.1016/0092-8674(76)90128-8