Crystal structure of the large ribosomal subunit from S. aureus

• US 10,556,934 B2
• Filed: 01/26/2016
• Issued: 02/11/2020
• Est. Priority Date: 01/29/2015
• Status: Active Grant

• Current Assignee: Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Original Assignee: Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Inventors: Yonath, Ada, Eyal, Zohar, Matzov, Donna, Rozenberg, Haim, Zimmerman, Ella, Bashan, Anat
• Primary Examiner(s): Noakes, Suzanne M
• Application Number:
  US15/547,499
• Publication Number:
  US 20180009853A1
• Time in Patent Office: 1,477 Days
• Field of Search: None
• CPC Class Codes: C07D 211/54 Sulfur atoms
• CPC Class Codes: C07D 263/20 attached in position 2
• CPC Class Codes: C07H 17/08 Hetero rings containing eight or more ring members, e.g. erythromycins
• CPC Class Codes: C07K 14/31 from Staphylococcus (G)
• CPC Class Codes: C07K 2299/00 Coordinates from 3D structures of peptides, e.g. proteins or enzymes
• CPC Class Codes: G16B 15/00 ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 15/20 Protein or domain folding
• CPC Class Codes: G16B 15/30 Drug targeting using structural data; Docking or binding prediction
• CPC Class Codes: G16B 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids
• CPC Class Codes: G16B 30/10 Sequence alignment; Homology search
• CPC Class Codes: G16B 35/00 ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides
• CPC Class Codes: G16C 20/50 Molecular design, e.g. of drugs
• CPC Class Codes: G16C 20/60 In silico combinatorial chemistry
• CPC Class Codes: G16C 20/62 Design of libraries

Abstract

A composition-of-matter comprising a crystallized form of a large ribosomal (50S) subunit of a pathogenic bacterium, and the atomic coordinates of the three-dimensional structure thereof are provided herein, as well as methods for crystallizing the same, and using the atomic coordinates of the same to design de novo ligands with high specificity thereto.

Claims

1. A composition-of-matter comprising a crystallized Staphylococcus aureus 50S large ribosomal subunit, wherein the crystallized 50S large ribosomal subunit effectively diffracts X-rays for calculating an electron density map and determination of atomic coordinates to a resolution of at least 4 Å

and forms in a hexagonal space group with unit cell dimensions of a=279.6±

10 Å

, b=279.6±

10 Å

, c=872.7±

10 Å

, α

, β

=90°

, γ

=120°

.

2. The composition of claim 1, wherein said Staphylococcus aureus is capable of developing a resistance to an antibacterial agent.

3. The composition of claim 2, wherein said Staphylococcus aureus is selected from the group consisting of a methicillin-resistant Staphylococcus aureus (MRSA), an oxacillin-resistant Staphylococcus aureus (ORSA), a vancomycin-resistant Staphylococcus aureus (VRSA) and a vancomycin intermediate Staphylococcus aureus (VISA).

4. The composition of claim 2, characterized by the atomic coordinates deposited at the Protein Data Bank under accession number PDB ID:

4WCE.

5. The composition of claim 1, wherein a ligand is bound to said large ribosomal subunit to form a crystallized complex of the subunit and said ligand.

6. The composition of claim 5, wherein said ligand is selected from the group consisting of linezolid, BC-3205, telithromycin, lefamulin and lincomycin.

7. The composition of claim 6, wherein said ligand is linezolid and the composition characterized by the atomic coordinates deposited at the Protein Data Bank under accession number PDB ID:

4WFA.

8. The composition of claim 6, wherein said ligand is BC-3205 and the composition characterized by the atomic coordinates deposited at the Protein Data Bank under accession number PDB ID:

4WFB.

9. The composition of claim 6, wherein said ligand is telithromycin and lincomycin and the composition characterized by the atomic coordinates deposited at the Protein Data Bank under accession number PDB ID:

4WF9.

10. The composition of claim 6, wherein said ligand is lefamulin and the composition characterized by the atomic coordinates deposited at the Protein Data Bank under accession number PDB ID:

5HL7.

11. The composition of claim 6, wherein said ligand is lincomycin and the composition characterized by the atomic coordinates deposited at the Protein Data Bank under accession number PDB ID:

5HKV.