Mechanism for Controlling the Dimer-Monomer Switch and Coupling Dimerization to Catalysis of the Severe Acute Respiratory Syndrome Coronavirus 3C-Like Protease

Shi, Jiahai; Sivaraman, J.; Song, Jianxing

doi:10.1128/jvi.02680-07

Cited by 159 publications

(258 citation statements)

References 32 publications

(56 reference statements)

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“…We thus speculated that this nano-channel plays a key role in allosterically relaying regulatory effects from the extra domain to the catalytic machinery located on the chymotrypsin fold (Shi and Song, 2006). Remarkably, this speculation has been strongly supported by our further structural and dynamic studies of the SARS 3C-like protease with both experimental and computational approaches (Shi et al, 2008(Shi et al, , 2011Lim et al, 2014).…”

Section: The Catalytic Machinery Is Under Extensive Regulation By Thementioning

confidence: 70%

Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses

Lim

Gupta

Roy

et al. 2019

Progress in Biophysics and Molecular Biology

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Coronavirus 3C-like and Flavivirus NS2B-NS3 proteases utilize the chymotrypsin fold to harbor their catalytic machineries but also contain additional domains/co-factors. Over the past decade, we aimed to decipher how the extra domains/co-factors mediate the catalytic machineries of SARS 3C-like, Dengue and Zika NS2B-NS3 proteases by characterizing their folding, structures, dynamics and inhibition with NMR, X-ray crystallography and MD simulations, and the results revealed: 1) the chymotrypsin fold of the SARS 3C-like protease can independently fold, while, by contrast, those of Dengue and Zika proteases lack the intrinsic capacity to fold without co-factors. 2) Mutations on the extra domain of SARS 3C-like protease can transform the active catalytic machinery into the inactive collapsed state by structurally-driven allostery. 3) Amazingly, even without detectable structural changes, mutations on the extra domain are sufficient to either inactivate or enhance the catalytic machinery of SARS 3C-like protease by dynamically-driven allostery. 4) Global networks of correlated motions have been identified: for SARS 3C-like protease, N214A inactivates the catalytic machinery by decoupling the network, while STI/A and STIF/A enhance by altering the patterns of the network. The global networks of Dengue and Zika proteases are coordinated by their NS2B-cofactors. 5) Natural products were identified to allosterically inhibit Zika and Dengue proteases through binding a pocket on the back of the active site. Therefore, by introducing extra domains/cofactors, nature develops diverse strategies to regulate the catalytic machinery embedded on the chymotrypsin fold through folding, structurally- and dynamically-driven allostery, all of which might be exploited to develop antiviral drugs.

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Section: The Catalytic Machinery Is Under Extensive Regulation By Thementioning

confidence: 70%

Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses

Lim

Gupta

Roy

et al. 2019

Progress in Biophysics and Molecular Biology

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“…The crystal was protected by the cryoprotectant (20% PEG 4000, 15% isopropyl alcohol, 25% glycol, and 0.1 M Hepes, pH 7.5). The data were indexed and scaled using the program d*Trek (37,38). After an all-space-group search, the crystal was identified as belonging to the space group P22 1 2 1 with a ϭ 53.75, b ϭ 71.12, and c ϭ 127.00 with two molecules per asymmetric unit.…”

Section: Methodsmentioning

confidence: 99%

“…Dynamic light scattering experiments were performed at 20°C on a DynaPro-MS/X instrument (Protein Solutions Inc.), and the apparent molecular mass values were calculated from 10 readings using the Protein Dynamics analysis software (43). Sedimentation velocity experiments were done at 20°C using a Beckman Coulter XL-I analytical ultracentrifuge as described previously (37).…”

Section: Methodsmentioning

confidence: 99%

Crystal Structure and NMR Binding Reveal That Two Small Molecule Antagonists Target the High Affinity Ephrin-binding Channel of the EphA4 Receptor

Qin

Shi

Noberini

et al. 2008

Journal of Biological Chemistry

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138

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The Eph receptor tyrosine kinases regulate a variety of physiological and pathological processes not only during development but also in adult organs, and therefore they represent a promising class of drug targets. The EphA4 receptor plays important roles in the inhibition of the regeneration of injured axons, synaptic plasticity, platelet aggregation, and likely in certain types of cancer. Here we report the first crystal structure of the EphA4 ligand-binding domain, which adopts the same jellyroll ␤-sandwich architecture as shown previously for EphB2 and EphB4. The similarity with EphB receptors is high in the core ␤-stranded regions, whereas large variations exist in the loops, particularly the D-E and J-K loops, which form the high affinity ephrin binding channel. We also used isothermal titration calorimetry, NMR spectroscopy, and computational docking to characterize the binding to EphA4 of two small molecules, 4-and 5-(2,5 dimethyl-pyrrol-1-yl)-2-hydroxybenzoic acid which antagonize ephrin-induced effects in EphA4-expressing cells. The erythropoietin-producing hepatocellular (Eph) 3 carcinoma receptors constitute the largest family of receptor tyrosine kinases, with 16 individual receptors throughout the animal kingdom, which are activated by nine ephrins (1-6). Eph receptors and their ligands are both anchored onto the plasma membrane and are subdivided into two subclasses (A and B) based on their sequence conservation and binding preferences. Usually, EphA receptors (EphA1-A10) interact with glycosylphosphatidylinositol-anchored ephrin-A ligands (ephrin-A1-A6), whereas EphB receptors (EphB1-B6) interact with transmembrane ephrin-B ligands (ephrin-B1-B3) that have a short cytoplasmic portion carrying both Src homology domain 2 and PDZ domain-binding motifs (7,8).The Eph receptors have a modular structure, consisting of a unique N-terminal ephrin-binding domain followed by a cysteine-rich linker and two fibronectin type III repeats in the extracellular region. The intracellular region is composed of a conserved tyrosine kinase domain, a C-terminal sterile ␣-domain, and a PDZ-binding motif. The N-terminal 180-residue globular domain of the Eph receptors has been shown to be sufficient for high affinity ephrin binding (9 -11). EphA subclass receptors remarkably differ from EphB receptors because they lack a 4-residue insert in the H-I loop of the ligand-binding domain. Previously, the structures of the EphB2 and EphB4 ligand-binding domains have been determined in both the free state and in complex with ephrins or peptide antagonists (10,11,(12)(13)(14)(15). These studies have shown that the ligand-binding domains of EphB2 and EphB4 adopt the same jellyroll ␤-sandwich architecture composed of 11 antiparallel ␤-strands connected by loops of various lengths. In particular, the D-E and * This work was supported by National Medical Research Council of Singapore Grant R-154-000-382-213 (to J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must the...

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“…This structural result is consistent with the observation that the contact between the amino acid at position 58 T and the catalytic cysteine has disappeared ( Table 1). Table S1, column 10), which forms several hydrogen bonds with the residues surrounding it, including the catalytic histidine [50].…”

Section: Ta [St]ψ and [Kr]p Groupsmentioning

confidence: 99%

“…As with the members of the prokaryotic TN group, viral serine/cysteine (chymo)trypsin-like fold proteases also have several members with an atypical NBCZone (Tables 2 and S2). They are: a putative serine protease (PDB ID: 2W5E, [69]), whose active site residues are not in the typical (chymo)trypsin-like conformation, and 4 additional proteins, non-structural protein NSP4 (PDB IDs: 5Y4L and 3FAN, [70,71]), 3C-like protease (PDB IDs: 5E0G and 5E0J, [72]), 3C-like proteinase (PDB IDs: 5C5O and 2QCY, [50,73]), and infectious bronchitis virus (IBV) main protease (PDB IDs: 2Q6F and 2Q6D, [74]), all of which demonstrate both a typical and atypical conformation of the dipeptide, residues 193 T -194 T .…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

NBCZone: Universal three-dimensional construction of eleven amino acids near the catalytic nucleophile and base in the superfamily of (chymo)trypsin-like serine fold proteases

Denesyuk

Johnson

Salo‐Ahen

et al. 2020

International Journal of Biological Macromolecules

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publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Journal Pre-proof NBCZone: Universal three-dimensional construction of eleven amino acids near the catalytic nucleophile and base in the superfamily of (chymo)trypsin-like serine fold proteases Please cite this article as: A.I. Denesyuk, M.S. Johnson, O.M.H. Salo-Ahen, et al., NBCZone: Universal three-dimensional construction of eleven amino acids near the catalytic nucleophile and base in the superfamily of (chymo)trypsin-like serine fold proteases, International Journal of Biological Macromolecules(2020), https://doi.Journal Pre-proof J o u r n a l P r e -p r o o f 2 Abstract(Chymo)trypsin-like serine fold proteases belong to the serine/cysteine proteases found in eukaryotes, prokaryotes, and viruses. Their catalytic activity is carried out using a triad of amino acids, a nucleophile, a base, and an acid. For this superfamily of proteases, we propose the existence of a universal 3D structure comprising 11 amino acids near the catalytic nucleophile and base -Nucleophile-Base Catalytic Zone (NBCZone). The comparison of NBCZones among 169 eukaryotic, prokaryotic, and viral (chymo)trypsin-like proteases suggested the existence of 15 distinct groups determined by the combination of amino acids located at two "key" structure-functional positions 54 T and 55 T near the catalytic base His57 T .Most eukaryotic and prokaryotic proteases fell into two major groups, [ST]A and TN.Usually, proteases of [ST]A group contain a disulfide bond between cysteines Cys42 T and Cys58 T of the NBCZone. In contrast, viral proteases were distributed among seven groups, and lack this disulfide bond. Furthermore, only the [ST]A group of eukaryotic proteases contains glycine at position 43 T , which is instrumental for activation of these enzymes. In contrast, due to the side chains of residues at position 43 T prokaryotic and viral proteases do not have the ability to carry out the structural transition of the eukaryotic zymogen-zyme type. Journal Pre-proof J o u r n a l P r e -p r o o f pattern G-[DE]-S-G-[GS] (https://prosite.expasy.org/; PROSITE documentation PDOC00124; TRYPSIN_SER, PS00135 [8]). In addition to this pattern, there is also a histidine active site pattern [LIVM]-[ST]-A-[STAG]-H-C (TRYPSIN_HIS, PS00134). In both families, the oxyanion hole is situated adjacent to the nucleophile and is mainly shaped by the main-chain nitrogen atoms of two residues, but again the sequential order is different. Knowing the importance of the existence of a catalytic acid, nucleophile, and oxyanion zones for the function of the α/β hydrolases fold enzymes and with the possible presence of similar structural formations in other types of hydrolases, we carried out a detailed analysis of the spatial structures of (chymo)trypsin-like serine fold prot...

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Mechanism for Controlling the Dimer-Monomer Switch and Coupling Dimerization to Catalysis of the Severe Acute Respiratory Syndrome Coronavirus 3C-Like Protease

Cited by 159 publications

References 32 publications

Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses

Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses

Crystal Structure and NMR Binding Reveal That Two Small Molecule Antagonists Target the High Affinity Ephrin-binding Channel of the EphA4 Receptor

NBCZone: Universal three-dimensional construction of eleven amino acids near the catalytic nucleophile and base in the superfamily of (chymo)trypsin-like serine fold proteases

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