7F0D

Cryo-EM structure of Mycobacterium tuberculosis 50S ribosome subunit bound with clarithromycin

Summary for 7F0D

• Entry DOI: 10.2210/pdb7f0d/pdb
• EMDB information: 31398
• Descriptor: 50S ribosomal protein L32, 50S ribosomal protein L3, 50S ribosomal protein L4, ... (34 entities in total)
• Functional Keywords: mycobacterium tuberculosis;50s ribosomal subunit;gate site a2062;clarithromycin; dynamic interaction;cryo-em;drug resistance, ribosome
• Biological source: Mycobacterium tuberculosis H37Ra; More
• Total number of polymer chains: 31
• Total formula weight: 1458903.71

Authors

Zhang, W.,Sun, Y.,Gao, N.,Li, Z. (deposition date: 2021-06-03, release date: 2022-06-29, Last modification date: 2024-06-12)

Primary citation

Zhang, W.,Li, Z.,Sun, Y.,Cui, P.,Liang, J.,Xing, Q.,Wu, J.,Xu, Y.,Zhang, W.,Zhang, Y.,He, L.,Gao, N.
Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides.
Emerg Microbes Infect, 11:293-305, 2022

PubMed Abstract: Tuberculosis (TB) is the leading infectious disease caused by (). Clarithromycin (CTY), an analog of erythromycin (ERY), is more potent against multidrug-resistance (MDR) TB. ERY and CTY were previously reported to bind to the nascent polypeptide exit tunnel (NPET) near peptidyl transferase center (PTC), but the only available CTY structure in complex with () ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for remains elusive since the ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 ( numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel -conformation as well as a swayed conformation bound with water molecule at interface, may play a role in coordinating the binding of specific drug molecules. The previously overlooked C-H hydrogen bond (H-bond) and π interaction may collectively contribute to the enhanced binding affinity. Together, our structure data provide a structural basis for the dynamic binding as well as the specificity of CTY and explain of how a single methyl group in CTY improves its potency, which provides new evidence to reveal previously unclear mechanism of translational modulation for future drug design and anti-TB therapy. Furthermore, our sample preparation method may facilitate drug discovery based on the complexes with low water solubility drugs by cryo-EM technique.

PubMed: 34935599
DOI: 10.1080/22221751.2021.2022439

Experimental method

ELECTRON MICROSCOPY (3.3 Å)