Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides

Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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...
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Autor*in:	Wen Zhang [verfasserIn] ZhiFei Li [verfasserIn] Yufan Sun [verfasserIn] Peng Cui [verfasserIn] Jianhua Liang [verfasserIn] Qinghe Xing [verfasserIn] Jing Wu [verfasserIn] Yanhui Xu [verfasserIn] Wenhong Zhang [verfasserIn] Ying Zhang [verfasserIn] Lin He [verfasserIn] Ning Gao [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	mycobacterium tuberculosis 50s ribosomal subunit clarithromycin gate site a2062 dynamic interaction cryo-em

Übergeordnetes Werk:	In: Emerging Microbes and Infections - Taylor & Francis Group, 2013, 11(2022), 1, Seite 293-305
Übergeordnetes Werk:	volume:11 ; year:2022 ; number:1 ; pages:293-305

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1080/22221751.2021.2022439

Katalog-ID:	DOAJ061474932

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allfields	10.1080/22221751.2021.2022439 doi (DE-627)DOAJ061474932 (DE-599)DOAJbe1b50b1e853475680b0ce3365d3c071 DE-627 ger DE-627 rakwb eng RC109-216 QR1-502 Wen Zhang verfasserin aut Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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 D. radiodurans (Dra) ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for Mtb remains elusive since the Mtb ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the Mtb ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 (E. coli numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel syn-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. mycobacterium tuberculosis 50s ribosomal subunit clarithromycin gate site a2062 dynamic interaction cryo-em Infectious and parasitic diseases Microbiology ZhiFei Li verfasserin aut Yufan Sun verfasserin aut Peng Cui verfasserin aut Jianhua Liang verfasserin aut Qinghe Xing verfasserin aut Jing Wu verfasserin aut Yanhui Xu verfasserin aut Wenhong Zhang verfasserin aut Ying Zhang verfasserin aut Lin He verfasserin aut Ning Gao verfasserin aut In Emerging Microbes and Infections Taylor & Francis Group, 2013 11(2022), 1, Seite 293-305 (DE-627)726120715 (DE-600)2681359-2 22221751 nnns volume:11 year:2022 number:1 pages:293-305 https://doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/article/be1b50b1e853475680b0ce3365d3c071 kostenfrei http://dx.doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/toc/2222-1751 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 1 293-305
spelling	10.1080/22221751.2021.2022439 doi (DE-627)DOAJ061474932 (DE-599)DOAJbe1b50b1e853475680b0ce3365d3c071 DE-627 ger DE-627 rakwb eng RC109-216 QR1-502 Wen Zhang verfasserin aut Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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 D. radiodurans (Dra) ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for Mtb remains elusive since the Mtb ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the Mtb ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 (E. coli numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel syn-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. mycobacterium tuberculosis 50s ribosomal subunit clarithromycin gate site a2062 dynamic interaction cryo-em Infectious and parasitic diseases Microbiology ZhiFei Li verfasserin aut Yufan Sun verfasserin aut Peng Cui verfasserin aut Jianhua Liang verfasserin aut Qinghe Xing verfasserin aut Jing Wu verfasserin aut Yanhui Xu verfasserin aut Wenhong Zhang verfasserin aut Ying Zhang verfasserin aut Lin He verfasserin aut Ning Gao verfasserin aut In Emerging Microbes and Infections Taylor & Francis Group, 2013 11(2022), 1, Seite 293-305 (DE-627)726120715 (DE-600)2681359-2 22221751 nnns volume:11 year:2022 number:1 pages:293-305 https://doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/article/be1b50b1e853475680b0ce3365d3c071 kostenfrei http://dx.doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/toc/2222-1751 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 1 293-305
allfields_unstemmed	10.1080/22221751.2021.2022439 doi (DE-627)DOAJ061474932 (DE-599)DOAJbe1b50b1e853475680b0ce3365d3c071 DE-627 ger DE-627 rakwb eng RC109-216 QR1-502 Wen Zhang verfasserin aut Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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 D. radiodurans (Dra) ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for Mtb remains elusive since the Mtb ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the Mtb ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 (E. coli numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel syn-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. mycobacterium tuberculosis 50s ribosomal subunit clarithromycin gate site a2062 dynamic interaction cryo-em Infectious and parasitic diseases Microbiology ZhiFei Li verfasserin aut Yufan Sun verfasserin aut Peng Cui verfasserin aut Jianhua Liang verfasserin aut Qinghe Xing verfasserin aut Jing Wu verfasserin aut Yanhui Xu verfasserin aut Wenhong Zhang verfasserin aut Ying Zhang verfasserin aut Lin He verfasserin aut Ning Gao verfasserin aut In Emerging Microbes and Infections Taylor & Francis Group, 2013 11(2022), 1, Seite 293-305 (DE-627)726120715 (DE-600)2681359-2 22221751 nnns volume:11 year:2022 number:1 pages:293-305 https://doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/article/be1b50b1e853475680b0ce3365d3c071 kostenfrei http://dx.doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/toc/2222-1751 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 1 293-305
allfieldsGer	10.1080/22221751.2021.2022439 doi (DE-627)DOAJ061474932 (DE-599)DOAJbe1b50b1e853475680b0ce3365d3c071 DE-627 ger DE-627 rakwb eng RC109-216 QR1-502 Wen Zhang verfasserin aut Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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 D. radiodurans (Dra) ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for Mtb remains elusive since the Mtb ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the Mtb ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 (E. coli numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel syn-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. mycobacterium tuberculosis 50s ribosomal subunit clarithromycin gate site a2062 dynamic interaction cryo-em Infectious and parasitic diseases Microbiology ZhiFei Li verfasserin aut Yufan Sun verfasserin aut Peng Cui verfasserin aut Jianhua Liang verfasserin aut Qinghe Xing verfasserin aut Jing Wu verfasserin aut Yanhui Xu verfasserin aut Wenhong Zhang verfasserin aut Ying Zhang verfasserin aut Lin He verfasserin aut Ning Gao verfasserin aut In Emerging Microbes and Infections Taylor & Francis Group, 2013 11(2022), 1, Seite 293-305 (DE-627)726120715 (DE-600)2681359-2 22221751 nnns volume:11 year:2022 number:1 pages:293-305 https://doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/article/be1b50b1e853475680b0ce3365d3c071 kostenfrei http://dx.doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/toc/2222-1751 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 1 293-305
allfieldsSound	10.1080/22221751.2021.2022439 doi (DE-627)DOAJ061474932 (DE-599)DOAJbe1b50b1e853475680b0ce3365d3c071 DE-627 ger DE-627 rakwb eng RC109-216 QR1-502 Wen Zhang verfasserin aut Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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 D. radiodurans (Dra) ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for Mtb remains elusive since the Mtb ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the Mtb ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 (E. coli numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel syn-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. mycobacterium tuberculosis 50s ribosomal subunit clarithromycin gate site a2062 dynamic interaction cryo-em Infectious and parasitic diseases Microbiology ZhiFei Li verfasserin aut Yufan Sun verfasserin aut Peng Cui verfasserin aut Jianhua Liang verfasserin aut Qinghe Xing verfasserin aut Jing Wu verfasserin aut Yanhui Xu verfasserin aut Wenhong Zhang verfasserin aut Ying Zhang verfasserin aut Lin He verfasserin aut Ning Gao verfasserin aut In Emerging Microbes and Infections Taylor & Francis Group, 2013 11(2022), 1, Seite 293-305 (DE-627)726120715 (DE-600)2681359-2 22221751 nnns volume:11 year:2022 number:1 pages:293-305 https://doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/article/be1b50b1e853475680b0ce3365d3c071 kostenfrei http://dx.doi.org/10.1080/22221751.2021.2022439 kostenfrei https://doaj.org/toc/2222-1751 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 1 293-305
language	English
source	In Emerging Microbes and Infections 11(2022), 1, Seite 293-305 volume:11 year:2022 number:1 pages:293-305
sourceStr	In Emerging Microbes and Infections 11(2022), 1, Seite 293-305 volume:11 year:2022 number:1 pages:293-305
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	mycobacterium tuberculosis 50s ribosomal subunit clarithromycin gate site a2062 dynamic interaction cryo-em Infectious and parasitic diseases Microbiology
isfreeaccess_bool	true
container_title	Emerging Microbes and Infections
authorswithroles_txt_mv	Wen Zhang @@aut@@ ZhiFei Li @@aut@@ Yufan Sun @@aut@@ Peng Cui @@aut@@ Jianhua Liang @@aut@@ Qinghe Xing @@aut@@ Jing Wu @@aut@@ Yanhui Xu @@aut@@ Wenhong Zhang @@aut@@ Ying Zhang @@aut@@ Lin He @@aut@@ Ning Gao @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	726120715
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callnumber-first	R - Medicine
author	Wen Zhang
spellingShingle	Wen Zhang misc RC109-216 misc QR1-502 misc mycobacterium tuberculosis misc 50s ribosomal subunit misc clarithromycin misc gate site a2062 misc dynamic interaction misc cryo-em misc Infectious and parasitic diseases misc Microbiology Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides
authorStr	Wen Zhang
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topic_title	RC109-216 QR1-502 Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides mycobacterium tuberculosis 50s ribosomal subunit clarithromycin gate site a2062 dynamic interaction cryo-em
topic	misc RC109-216 misc QR1-502 misc mycobacterium tuberculosis misc 50s ribosomal subunit misc clarithromycin misc gate site a2062 misc dynamic interaction misc cryo-em misc Infectious and parasitic diseases misc Microbiology
topic_unstemmed	misc RC109-216 misc QR1-502 misc mycobacterium tuberculosis misc 50s ribosomal subunit misc clarithromycin misc gate site a2062 misc dynamic interaction misc cryo-em misc Infectious and parasitic diseases misc Microbiology
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title	Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides
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title_full	Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides
author_sort	Wen Zhang
journal	Emerging Microbes and Infections
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author_browse	Wen Zhang ZhiFei Li Yufan Sun Peng Cui Jianhua Liang Qinghe Xing Jing Wu Yanhui Xu Wenhong Zhang Ying Zhang Lin He Ning Gao
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title_sort	cryo-em structure of mycobacterium tuberculosis 50s ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides
callnumber	RC109-216
title_auth	Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides
abstract	Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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 D. radiodurans (Dra) ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for Mtb remains elusive since the Mtb ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the Mtb ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 (E. coli numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel syn-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.
abstractGer	Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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 D. radiodurans (Dra) ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for Mtb remains elusive since the Mtb ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the Mtb ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 (E. coli numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel syn-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.
abstract_unstemmed	Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis (Mtb). 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 D. radiodurans (Dra) ribosome could be misinterpreted due to resolution limitation. To date, the mechanism of specificity and efficacy of CTY for Mtb remains elusive since the Mtb ribosome-CTY complex structure is still unknown. Here, we employed new sample preparation methods and solved the Mtb ribosome-CTY complex structure at 3.3Å with cryo-EM technique, where the crucial gate site A2062 (E. coli numbering) is located at the CTY binding site within NPET. Two alternative conformations of A2062, a novel syn-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.
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title_short	Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides
url	https://doi.org/10.1080/22221751.2021.2022439 https://doaj.org/article/be1b50b1e853475680b0ce3365d3c071 http://dx.doi.org/10.1080/22221751.2021.2022439 https://doaj.org/toc/2222-1751
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Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides

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