PDBsum entry 1k9m

Ribosome

PDB id: 1k9m

Contents

Protein chains

237 a.a. *

337 a.a. *

246 a.a. *

140 a.a. *

172 a.a. *

119 a.a. *

29 a.a. *

156 a.a. *

142 a.a. *

132 a.a. *

145 a.a. *

194 a.a. *

186 a.a. *

115 a.a. *

143 a.a. *

95 a.a. *

150 a.a. *

81 a.a. *

119 a.a. *

53 a.a. *

65 a.a. *

154 a.a. *

82 a.a. *

142 a.a. *

73 a.a. *

56 a.a. *

46 a.a. *

92 a.a. *

DNA/RNA

Ligands

TYK

Metals

__K ×3

_NA ×85

_CL ×22

_MG ×119

_CD ×5

Waters ×7877

* Residue conservation analysis

References listed in PDB file

Key reference

Title

The structures of four macrolide antibiotics bound to the large ribosomal subunit.

Authors

J.L.Hansen, J.A.Ippolito, N.Ban, P.Nissen, P.B.Moore, T.A.Steitz.

Ref.

Mol Cell, 2002, 10, 117-128. [DOI no: 10.1016/S1097-2765(02)00570-1]

PubMed id

12150912

Abstract

Crystal structures of the Haloarcula marismortui large ribosomal subunit complexed with the 16-membered macrolide antibiotics carbomycin A, spiramycin, and tylosin and a 15-membered macrolide, azithromycin, show that they bind in the polypeptide exit tunnel adjacent to the peptidyl transferase center. Their location suggests that they inhibit protein synthesis by blocking the egress of nascent polypeptides. The saccharide branch attached to C5 of the lactone rings extends toward the peptidyl transferase center, and the isobutyrate extension of the carbomycin A disaccharide overlaps the A-site. Unexpectedly, a reversible covalent bond forms between the ethylaldehyde substituent at the C6 position of the 16-membered macrolides and the N6 of A2103 (A2062, E. coli). Mutations in 23S rRNA that result in clinical resistance render the binding site less complementary to macrolides.

Figure 1.
Figure 1. Chemical Structures of the Macrolides, Tylosin, Carbomycin A, Spiramycin, Azithromycin, and ErythromycinAtoms in these figures and in the Protein Data Bank coordinate files (1K8A, 1K9M, 1M1K, and 1KD1) are named according to Paesen et al. (1995), with the numbering of the atoms of the lactone ring starting at the ester bond. Oxygen atoms are numbered according to the adjacent carbon atoms, and sugar atom numbers are modified by suffixes A, B, or C to distinguish mycaminose, mycarose, and any additional sugar, respectively.

Figure 5.
Figure 5. Comparison of the Interactions of Different Macrolides with the Ribosome(A) Carbomycin (red), tylosin (orange), spiramycin (yellow), and azithromycin (blue) bind the ribosome in an almost identical fashion and cover G2099 (A2058) and A2100 (2059) (green spheres). The lactone ring is extended further into the tunnel by mycinose on tylosin and forosamine on spiramycin. The disaccharide moiety extends the 16-membered macrolides in the opposite direction toward the catalytic center. Upon 16-membered macrolide binding (but not azithromycin), the base of A2103 (2062) (dark green) moves (curved white line) from its location against the wall of the exit tunnel to an extended conformation (light green sticks) and forms a covalent bond with the macrolide (orange sticks). The isobutyrate group of carbomycin A (red) reaches into the tRNA A-site (dark blue and purple spheres). The mycinose moiety of tylosin (orange) contacts protein L22. The forosamine moiety of spiramycin (yellow) contacts L4. The cladinose sugar of azithromycin binds in a fourth sugar binding pocket. These three macrolides were aligned by least squares superimposition of the phosphates of ribosomal RNA.(B) Alignment of erythromycin (white) bound to the D. radiodurans large subunit (Schlünzen et al., 2001) with azithromycin (blue) bound to the H. marismortui large subunit.

The above figures are reprinted by permission from Cell Press: Mol Cell (2002, 10, 117-128) copyright 2002.