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Broad spectrum antibiotic-degrading metallo-β-lactamases are phylogenetically diverse

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Protein & Cell 2020年第8期11卷 613-617页

作者： Marcelo Monteiro Pedroso David w.waite Okke Melse Liam wilson Natasa Mitic Ross P.McGeary Iris Antes luke w.guddat Philip Hugenholtz Gerhard Schenk School of Chemistry and Molecular Biosciences The University of QueenslandSt.LuciaQLDBrisbane 4072Australia Australian Centre for Ecogenomics The University of QueenslandSt.LuciaQLDBrisbane 4072Australia Center for Integrated Protein Science Munich at the TUM School of Life Sciences Technische Universit(a)t München85354 FreisingGermany Department of Chemistry Maynooth UniversityMaynoothCo.KildareIreland

Dear Editor, Antibiotic resistance has emerged as a major threat to global health;multi-drug resistant bacteria already kill more patients in the United States each year than HIV/AIDS, Parkinson's disease, emphysema and homicide combined (Laxminarayan et al., 2013).Among the most effective bacterial resistance mechanisms are β-lactamases, a family of enzymes that are divided into four distinct *** A, C and D (serine-β-lactamases, SBLs) use a catalytic site serine residue to initiate inactivation of the antibiotic, while Class B (metallo-β-lactamases, MBLs) relies on a Zn2+-activated hydroxide (walsh et al., 2005;Bush and Jacoby,2010;Mitic et al., 2014;Lisa et al., 2017).Clinically relevant inhibitors of Class C and D SBLs are available and in use (e.g., clavulanic acid (CA), Drawz et al., 2010), but for MBLs the search for such inhibitors has remained challenging (McGeary et al., 2017).

关键词： hydroxide metallo spectrum

Cryo-EM structures of a prokaryotic heme transporter CydDC

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维普期刊数据库

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Protein & Cell 2023年第12期14卷 919-923页

作者： Chen Zhu Yanfeng Shi Jing Yu wenhao Zhao Lingqiao Li Jingxi Liang Xiaolin Yang Bing Zhang Yao Zhao Yan Gao Xiaobo Chen Xiuna Yang Lu Zhang luke w.guddat Lei Liu Haitao Yang Zihe Rao Jun Li Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China National Clinical Research Center for Infectious Disease Shenzhen Third People's HospitalShenzhen 518112China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300353China Innovative Centerfor Pathogen Research Guangzhou LaboratoryGuangzhou 510005China School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQLD 4072Australia

DearEditor,Heme is an essential cofactor required across all kingdoms of life utilized in numerous biological processes,including cellular *** is a prokaryotic ATP-binding cassette(ABC)transporter required for heme assembling in respiratory cytochrome bd oxidase(Georgiou et al.,1987;Poole et al.,1989),a promising target for drug discovery(Borisov et al.,2011).CydDC is thought to play a role in maintaining an optimum periplasmic redox poise that is required for the incorporation of heme cofactors(Yamashita et al.,2014).It also suggested that CydDC is involved in heme processing by mediating glutathione/cysteine translocation(Cook and Poole,2000;Cook et al.,2002),although a role in heme translocation seems unlikely(Yamashita et al.,2014).To date,CydDC has been shown to be important for disulfide bond formation,motility,respiration,and tolerance to nitric oxide and antibiotics(Poole et al.,2019).

关键词： utilized disulfide Poole

Cryo-EM snapshots of mycobacterial arabinosyltransferase complex EmbB2-AcpM2

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Protein & Cell 2020年第7期11卷 505-517页

作者： Lu Zhang Yao Zha Ruogu Gao Jun Li Xiuna Yang Yan Gao wei Zhao Sudagar S.Gurcha Natacha Veerapen Sarah M.Batt Kajelle Kaur Besra wenqing Xu Lijun Bi Xian'en Zhang luke w.guddat Haitao Yang Quan wang Gurdyal S.Besra Zihe Rao State Key Laboratory of Medicinal Chemical Biology College of Life Sciences and College of PharmacyNankai UniversityTianjin 300353China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell BiologyChinese Academy of Sciences(CAS)Shanghai 200031China University of Chinese Academy of Sciences Beijing 100101China National Laboratory of Biomacromolecules and Key Laboratory of RNA Biology CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsCASBeijing 100101China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China School of Biosciences Institute of Microbiology and InfectionUniversity of BirminghamBirmingham B152TTUK School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQLD 4072Australia

Inhibition of Mycobacterium tuberculosis(Mtb)cell wall assembly is an established strategy for anti-TB *** EmbB,which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose(DPA)to its arabinosyl acceptor is an essential enzyme for Mtb cell wall *** of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug,***,we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its"resting state"and DPA-bound"active state".EmbB is a fifteen-transmembrane-spanning protein,assembled as a *** protomer has an associated acyl-carrier-protein(AcpM)on their cytoplasmic ***-mational changes upon DPA binding indicate an asym-metric movement within the EmbB dimer during *** studies have identified critical residues in substrate recognition and catalysis,and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with *** structures represent the first step directed towards a rational approach for anti-TB drug discovery.

关键词： Mycobacterium tuberculosis EmbB cryo-EM ethambutol cell wall synthesis arabinoglacatan arabinosyltransferase acyl-carrier-protein drug discovery

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors

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Protein & Cell 2021年第11期12卷 877-888页

作者： Yao Zhao Xiaoyu Du Yinkai Duan Xiaoyan Pan Yifang Sun Tian You Lin Han Zhenming Jin weijuan Shang Jing Yu Hangtian Guo Qianying Liu Yan wu Chao Peng Jun wang Chenghao Zhu Xiuna Yang Kailin Yang Ying Lei luke w.guddat wenqing Xu Gengfu Xiao Lei Sun Leike Zhang Zihe Rao Haitao Yang Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Laboratory of Structural Biology School of Life Sciences and School of MedicineTsinghua UniversityBeijing 100091China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China The Fifth People's Hospital of Shanghai Fudan University and Shanghai Key Laboratory of Medical EpigeneticsInstitutes of Biomedical SciencesFudan UniversityShanghai 200032China Zhangjiang Lab National Facility for Protein Science in ShanghaiShanghai Advanced Research InstituteChinese Academy of ScienceShanghai 201210China Taussig Cancer Center Cleveland ClinicClevelandOH 44195USA School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQueensland 4072Australia

A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 ***,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 *** this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional ***-fore,it is an attractive target for antiviral drug *** we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/*** compounds also exhibit strong antiviral activities in cell-based ***155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/*** addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding ***155 simultaneously targets three"hot"spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger *** results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

关键词： SARS-CoV-2 papain-like protease YM155 interferon stimulating gene product 15 drug repurposing

Structural insights into substrate recognition by the type Ⅶ secretion system

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Protein & Cell 2020年第2期11卷 124-137页

作者： Shuhui wang Kaixuan Zhou Xiaolin Yang Bing Zhang Yao Zhao Yu Xiao Xiuna Yang Haitao Yang luke wguddat Jun Li Zihe Rao Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China State Key Laboratory of Medicinal Chemical Biology College of Life Sciences and College of PharmacyNankai UniversityTianjin 300353China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQLD 4072Australia University of Chinese Academy of Sciences Beijing 100101China

Type VII secretion systems(T7SSs)are found in many disease related bacteria including Mycobacterium tuberculosis(Mtb).ESX-1[early secreted antigen 6 kilodaltons(ESAT-6)system 1]is one of the five subtypes(ESX-1?5)of T7SSs in Mfb,where it delivers virulence factors into host macrophages during ***,little is known about the molecular details as to how this ***,we provide high-resolution crystal structures of the C-terminal ATPase3 domains of EccC subunits from four different Mtb T7SS *** structures adopt a classic RecA-like a/p fold with a conserved Mg-ATP binding *** structure of EccCbl in complex with the C-terminal peptide of EsxB identifies the location of substrate recognition site and shows how the specific signaling module XxxxMxF"for Mtb ESX-1 binds to this site resulting in a translation of the bulge loop.A comparison of all the ATPase3 structures shows there are significant differences in the shape and composition of the signal recognition pockets across the family,suggesting that distinct signaling sequences of substrates are required to be specifically recognized by different T7SSs.A hexameric model of the EccC-ATPase3 is proposed and shows the recognition pocket is located near the central substrate translocation *** diameter of the channel is?25-A,with a size that would allow helix-bundle shaped substrate proteins to bind and pass ***,our work provides new molecular insights into substrate recognition for Mtb T7SS subtypes and also a possible transportation mechanism for substrate and/or virulence factor secretion.

关键词： type VII secretion system Mycobacterium tuberculosis ATPase virulence factor substrate recognition

Cryo-EM structures for the Mycobacterium tuberculosis iron-loaded siderophore transporter IrtAB

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Protein & Cell 2023年第6期14卷 448-458页

作者： Shan Sun Yan Gao Xiaolin Yang Xiuna Yang Tianyu Hu Jingxi Liang Zhiqi Xiong Yuting Ran Pengxuan Ren Fang Bai luke wguddat Haitao Yang Zihe Rao Bing Zhang Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300353China Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China School of Chemistry and Molecular Biosciences The University of QueenslandBrisbaneQueensland 4072Australia CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100101China Shanghai Clinical Research and Trial Center Shanghai 201210China

The adenosine 5'-triphosphate(ATP)-binding cassette(ABC)transporter,IrtAB,plays a vital role in the replication and viability of Mycobacterium tuberculosis(Mtb),where its function is to import iron-loaded ***,it adopts the canonical type IV exporter ***,we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP,ADP,or ATP analogue(AMP-PNP)at resolutions ranging from 2.8 to 3.5Å.The structure of IrtAB bound ATP-Mg2+shows a“head-to-tail”dimer of nucleotide-binding domains(NBDs),a closed amphipathic cavity within the transmembrane domains(TMDs),and a metal ion liganded to three histidine residues of IrtA in the ***-electron microscopy(Cryo-EM)structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with ***,the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport *** study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.

关键词： ABC exporter-like importer iron-loaded siderophore IrtAB Mycobacterium tuberculosis ABC transporter

不对称芳香二硫醚类AHAS抑制剂的设计、合成与生物活性

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不对称芳香二硫醚类AHAS抑制剂的设计、合成与生物活性

Structure-function Relationships in Human Hypoxanthine-guanine Phosphoribosyltransferase(HGPRT) by Random Mutagenesis

中国化学会第28届学术年会

作者：王建国王伟民尚君李永红牛聪伟商建丽宋海斌席真李正名 luke w.guddat 南开大学元素有机化学研究所元素有机化学国家重点实验室澳大利亚昆士兰大学化学与生命科学学院

＜正＞乙酰乳酸合成酶（acetohydroxyacid synthase,AHAS）催化支链氨基酸的生物合成,是对人畜等安全的除草剂作用靶点1,随着已有除草剂出现的抗性问题2,研究新颖结构的AHAS抑制剂具有重大意义。本小组前期基于AHAS的复合物晶体,经过虚... 详细信息

＜正＞乙酰乳酸合成酶（acetohydroxyacid synthase,AHAS）催化支链氨基酸的生物合成,是对人畜等安全的除草剂作用靶点1,随着已有除草剂出现的抗性问题2,研究新颖结构的AHAS抑制剂具有重大意义。本小组前期基于AHAS的复合物晶体,经过虚拟筛选发现了一些新结构的AHAS抑制剂3。依此我们

关键词：乙酰乳酸合成酶除草剂不对称二硫醚合成生物活性

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cnki会议

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Chemical Research in Chinese Universities 2006年第2期22卷 251-252页

作者： luke guddat Anthony Farlow John de Jersey Department of Biochemistry and Molecular Biology University of Queensland St Lucia Queensland 4072 Australia

Hypoxanthine-guanine phosphoribosyltransferase （ HGPRT, EC 2.***.2.8） is a key enzyme of the purine salvage pathway, which allows recycling of purine bases into DNA and RNA. It is widely distributed in nature and has been studied both in prokaryotes and eukaryotes. In humans, a complete lack of HGPRT activity causes the Lesch-Nyhan syndrome, which is characterized by hyperuricaemia and neural disorders,

关键词： Hypoxanthine-guanine phosphoribosyltransferase Random mutagenesis Structure-function relationship

Mammalian-like Purple Acid Phosphatases in Plants

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Chemical Research in Chinese Universities 2006年第2期22卷 263-264页

作者： John de Jersey FAN Hong-kuan Gary Schenk luke guddat Susan Hamilton Department of Biochemistry and Molecular Biology University of Queensland St Lucia Queensland 4072 Australia

Introduction Purple acid phosphatases （PAPs） comprise of a family of binuclear metal-containing hydrolases, some members of which have been isolated and characterized from animal, plant and fungal sources . PAPs not only catalyze the hydrolyses of a wide range of phosphate esters and anhydrides under acidic reaction conditions, but also catalyze the generation of hydroxyl radicals in a Fenton-like reaction, by virtue of the presence of a redox-active binuclear metal center. Inmammals,

关键词： Purple acid phosphatase Mammalian-like GST-fusion protein