5RFD

PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 main protease in complex with Z126932614

PDB DOI: https://doi.org/10.2210/pdb5RFD/pdb
Deposition Group: G_1002151 (changed state) ExploreG_1002151

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Severe acute respiratory syndrome coronavirus 2
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2020-03-15 Released: 2020-03-25
Deposition Author(s): Fearon, D., Owen, C.D., Douangamath, A., Lukacik, P., Powell, A.J., Strain-Damerell, C.M., Resnick, E., Krojer, T., Gehrtz, P., Wild, C., Aimon, A., Brandao-Neto, J., Carbery, A., Dunnett, L., Skyner, R., Snee, M., London, N., Walsh, M.A., von Delft, F.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.41 Å
R-Value Free: 0.211
R-Value Work: 0.178
R-Value Observed: 0.179

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.5 of the entry. See complete history.

Literature

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.

Douangamath, A., Fearon, D., Gehrtz, P., Krojer, T., Lukacik, P., Owen, C.D., Resnick, E., Strain-Damerell, C., Aimon, A., Abranyi-Balogh, P., Brandao-Neto, J., Carbery, A., Davison, G., Dias, A., Downes, T.D., Dunnett, L., Fairhead, M., Firth, J.D., Jones, S.P., Keeley, A., Keseru, G.M., Klein, H.F., Martin, M.P., Noble, M.E.M., O'Brien, P., Powell, A., Reddi, R.N., Skyner, R., Snee, M., Waring, M.J., Wild, C., London, N., von Delft, F., Walsh, M.A.

(2020) Nat Commun 11: 5047-5047

PubMed: 33028810 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/s41467-020-18709-w
Primary Citation of Related Structures:
5R7Y, 5R7Z, 5R80, 5R81, 5R82, 5R83, 5R84, 5RE4, 5RE5, 5RE6, 5RE7, 5RE8, 5RE9, 5REA, 5REB, 5REC, 5RED, 5REE, 5REF, 5REG, 5REH, 5REI, 5REJ, 5REK, 5REL, 5REM, 5REN, 5REO, 5REP, 5RER, 5RES, 5RET, 5REU, 5REV, 5REW, 5REX, 5REY, 5REZ, 5RF0, 5RF1, 5RF2, 5RF3, 5RF4, 5RF5, 5RF6, 5RF7, 5RF8, 5RF9, 5RFA, 5RFB

PubMed Abstract:
COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

Organizational Affiliation

Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0QX, UK.

Macromolecule Content

Total Structure Weight: 34.27 kDa
Atom Count: 2,728
Modelled Residue Count: 304
Deposited Residue Count: 306
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
3C-like proteinase	A	306	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 0 Gene Names: rep, 1a-1b EC: 3.4.22.69
UniProt
Find proteins for P0DTD1 (Severe acute respiratory syndrome coronavirus 2) Explore P0DTD1 Go to UniProtKB: P0DTD1
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P0DTD1
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
T6J (Subject of Investigation/LOI) Query on T6J Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	2-[(methylsulfonyl)methyl]-1H-benzimidazole C₉ H₁₀ N₂ O₂ S WCWTYTQSZZWNEW-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain B [auth A] SDF format, chain C [auth A] SDF format, chain D [auth A] MOL2 format, chain B [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] mmCIF format, chain B [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A]	B [auth A], C [auth A], D [auth A]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A] Interactions & Density Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.41 Å
R-Value Free: 0.211
R-Value Work: 0.178
R-Value Observed: 0.179
Space Group: C 1 2 1
Diffraction Data: https://doi.org/10.5281/zenodo.3731341

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 111.952	α = 90
b = 52.63	β = 102.98
c = 44.657	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
Aimless	data scaling
PDB_EXTRACT	data extraction
XDS	data reduction
REFMAC	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2020-03-25

Deposition Author(s):

Strain-Damerell, C.M.

Revision History (Full details and data files)

Version 1.0: 2020-03-25
Type: Initial release
Version 1.1: 2020-04-08
Changes: Database references, Structure summary
Version 1.2: 2020-05-06
Changes: Database references, Source and taxonomy, Structure summary
Version 1.3: 2021-01-27
Changes: Structure summary
Version 1.4: 2021-02-24
Changes: Database references
Version 1.5: 2024-03-06
Changes: Data collection, Database references