B. Wiseman, R. Nitharwal, O. Fedotovskaya, Jacob Schäfer, Hui Guo, Qie Kuang, S. Benlekbir, D. Sjöstrand, Pia Ädelroth, J. Rubinstein, P. Brzezinski, M. Högbom
{"title":"Structure of a functional obligate respiratory supercomplex from Mycobacterium smegmatis","authors":"B. Wiseman, R. Nitharwal, O. Fedotovskaya, Jacob Schäfer, Hui Guo, Qie Kuang, S. Benlekbir, D. Sjöstrand, Pia Ädelroth, J. Rubinstein, P. Brzezinski, M. Högbom","doi":"10.2210/pdb6hwh/pdb","DOIUrl":"https://doi.org/10.2210/pdb6hwh/pdb","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"1128-1136"},"PeriodicalIF":16.8,"publicationDate":"2018-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43068937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Marcos, T. M. Chidyausiku, A. McShan, T. Evangelidis, S. Nerli, N. Sgourakis, K. Tripsianes, D. Baker
{"title":"Solution NMR structure of a de novo designed double-stranded beta-helix","authors":"E. Marcos, T. M. Chidyausiku, A. McShan, T. Evangelidis, S. Nerli, N. Sgourakis, K. Tripsianes, D. Baker","doi":"10.2210/pdb6e5c/pdb","DOIUrl":"https://doi.org/10.2210/pdb6e5c/pdb","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"1 1","pages":""},"PeriodicalIF":16.8,"publicationDate":"2018-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68198532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Human sigma-1 receptor bound to (+)-pentazocine","authors":"H. Schmidt, Robin M. Betz, R. Dror, A. Kruse","doi":"10.2210/PDB6DK1/PDB","DOIUrl":"https://doi.org/10.2210/PDB6DK1/PDB","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"981-987"},"PeriodicalIF":16.8,"publicationDate":"2018-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48599379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Nemoz, V. Ropars, P. Frit, A. Gontier, P. Drevet, J. Yu, R. Guérois, A. Pitois, A. Comte, C. Delteil, N. Barboule, Pierre Legrand, S. Baconnais, Y. Yin, S. Tadi, E. Barbet-Massin, I. Berger, E. Cam, M. Modesti, E. Rothenberg, P. Calsou, J. Charbonnier
The Ku70-Ku80 (Ku) heterodimer binds rapidly and tightly to the ends of DNA double-strand breaks and recruits factors of the non-homologous end-joining (NHEJ) repair pathway through molecular interactions that remain unclear. We have determined crystal structures of the Ku-binding motifs (KBM) of the NHEJ proteins APLF (A-KBM) and XLF (X-KBM) bound to a Ku-DNA complex. The two KBM motifs bind remote sites of the Ku80 α/β domain. The X-KBM occupies an internal pocket formed by an unprecedented large outward rotation of the Ku80 α/β domain. We observe independent recruitment of the APLF-interacting protein XRCC4 and of XLF to laser-irradiated sites via binding of A- and X-KBMs, respectively, to Ku80. Finally, we show that mutation of the X-KBM and A-KBM binding sites in Ku80 compromises both the efficiency and accuracy of end joining and cellular radiosensitivity. A- and X-KBMs may represent two initial anchor points to build the intricate interaction network required for NHEJ.
Ku70-Ku80 (Ku)异二聚体与DNA双链断裂末端快速紧密结合，并通过分子相互作用招募非同源末端连接(NHEJ)修复途径的因子，目前尚不清楚。我们已经确定了与Ku-DNA复合物结合的NHEJ蛋白APLF (a -KBM)和XLF (X-KBM)的ku结合基序(KBM)的晶体结构。这两个KBM基序结合Ku80 α/β结构域的远端位点。X-KBM占据了Ku80 α/β结构域前所未有的大向外旋转形成的内部口袋。我们观察到与aplf相互作用的蛋白XRCC4和XLF分别通过A-和X-KBMs与Ku80的结合而独立募集到激光照射位点。最后，我们发现Ku80中X-KBM和A-KBM结合位点的突变会影响末端连接的效率和准确性以及细胞放射敏感性。A-和X-KBMs可能是构建NHEJ所需的复杂相互作用网络的两个初始锚点。
{"title":"Complex of APLF factor and Ku heterodimer bound to DNA","authors":"C. Nemoz, V. Ropars, P. Frit, A. Gontier, P. Drevet, J. Yu, R. Guérois, A. Pitois, A. Comte, C. Delteil, N. Barboule, Pierre Legrand, S. Baconnais, Y. Yin, S. Tadi, E. Barbet-Massin, I. Berger, E. Cam, M. Modesti, E. Rothenberg, P. Calsou, J. Charbonnier","doi":"10.2210/PDB6ERF/PDB","DOIUrl":"https://doi.org/10.2210/PDB6ERF/PDB","url":null,"abstract":"The Ku70-Ku80 (Ku) heterodimer binds rapidly and tightly to the ends of DNA double-strand breaks and recruits factors of the non-homologous end-joining (NHEJ) repair pathway through molecular interactions that remain unclear. We have determined crystal structures of the Ku-binding motifs (KBM) of the NHEJ proteins APLF (A-KBM) and XLF (X-KBM) bound to a Ku-DNA complex. The two KBM motifs bind remote sites of the Ku80 α/β domain. The X-KBM occupies an internal pocket formed by an unprecedented large outward rotation of the Ku80 α/β domain. We observe independent recruitment of the APLF-interacting protein XRCC4 and of XLF to laser-irradiated sites via binding of A- and X-KBMs, respectively, to Ku80. Finally, we show that mutation of the X-KBM and A-KBM binding sites in Ku80 compromises both the efficiency and accuracy of end joining and cellular radiosensitivity. A- and X-KBMs may represent two initial anchor points to build the intricate interaction network required for NHEJ.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"971-980"},"PeriodicalIF":16.8,"publicationDate":"2018-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43524372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mingfeng Zhang, Dali Wang, Yunlu Kang, Jing-Xiang Wu, Fuqiang Yao, Chengfang Pan, Zhiqiang Yan, Chen Song, Lei Chen
Mechanosensitive ion channels convert mechanical stimuli into a flow of ions. These channels are widely distributed from bacteria to higher plants and humans, and are involved in many crucial physiological processes. Here we show that two members of the OSCA protein family in Arabidopsis thaliana, namely AtOSCA1.1 and AtOSCA3.1, belong to a new class of mechanosensitive ion channels. We solve the structure of the AtOSCA1.1 channel at 3.5-A resolution and AtOSCA3.1 at 4.8-A resolution by cryo-electron microscopy. OSCA channels are symmetric dimers that are mediated by cytosolic inter-subunit interactions. Strikingly, they have structural similarity to the mammalian TMEM16 family proteins. Our structural analysis accompanied with electrophysiological studies identifies the ion permeation pathway within each subunit and suggests a conformational change model for activation.
{"title":"Structure of atOSCA3.1 channel","authors":"Mingfeng Zhang, Dali Wang, Yunlu Kang, Jing-Xiang Wu, Fuqiang Yao, Chengfang Pan, Zhiqiang Yan, Chen Song, Lei Chen","doi":"10.2210/PDB5Z1F/PDB","DOIUrl":"https://doi.org/10.2210/PDB5Z1F/PDB","url":null,"abstract":"Mechanosensitive ion channels convert mechanical stimuli into a flow of ions. These channels are widely distributed from bacteria to higher plants and humans, and are involved in many crucial physiological processes. Here we show that two members of the OSCA protein family in Arabidopsis thaliana, namely AtOSCA1.1 and AtOSCA3.1, belong to a new class of mechanosensitive ion channels. We solve the structure of the AtOSCA1.1 channel at 3.5-A resolution and AtOSCA3.1 at 4.8-A resolution by cryo-electron microscopy. OSCA channels are symmetric dimers that are mediated by cytosolic inter-subunit interactions. Strikingly, they have structural similarity to the mammalian TMEM16 family proteins. Our structural analysis accompanied with electrophysiological studies identifies the ion permeation pathway within each subunit and suggests a conformational change model for activation.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"850-858"},"PeriodicalIF":16.8,"publicationDate":"2018-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49209488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. McCorvy, Daniel Wacker, Sheng Wang, B. Agegnehu, Jing Liu, Katherine Lansu, A. Tribo, Reid H. J. Olsen, T. Che, Jian Jin, B. Roth
{"title":"Structural Determinants of Activation and Biased Agonism at the 5-HT2B Receptor","authors":"J. McCorvy, Daniel Wacker, Sheng Wang, B. Agegnehu, Jing Liu, Katherine Lansu, A. Tribo, Reid H. J. Olsen, T. Che, Jian Jin, B. Roth","doi":"10.2210/PDB6DRX/PDB","DOIUrl":"https://doi.org/10.2210/PDB6DRX/PDB","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"787-796"},"PeriodicalIF":16.8,"publicationDate":"2018-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49588851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transient receptor potential vanilloid subfamily member 3 (TRPV3) channel plays a crucial role in skin physiology and pathophysiology. Mutations in TRPV3 are associated with various skin diseases, including Olmsted syndrome, atopic dermatitis, and rosacea. Here we present the cryo-electron microscopy structures of full-length mouse TRPV3 in the closed apo and agonist-bound open states. The agonist binds three allosteric sites distal to the pore. Channel opening is accompanied by conformational changes in both the outer pore and the intracellular gate. The gate is formed by the pore-lining S6 helices that undergo local α-to-π helical transitions, elongate, rotate, and splay apart in the open state. In the closed state, the shorter S6 segments are entirely α-helical, expose their nonpolar surfaces to the pore, and hydrophobically seal the ion permeation pathway. These findings further illuminate TRP channel activation and can aid in the design of drugs for the treatment of inflammatory skin conditions, itch, and pain.
{"title":"Cryo-EM structure of mouse TRPV3 in complex with 2-Aminoethoxydiphenyl borate (2-APB)","authors":"A. Singh, L. L. McGoldrick, A. Sobolevsky","doi":"10.2210/PDB6DVY/PDB","DOIUrl":"https://doi.org/10.2210/PDB6DVY/PDB","url":null,"abstract":"Transient receptor potential vanilloid subfamily member 3 (TRPV3) channel plays a crucial role in skin physiology and pathophysiology. Mutations in TRPV3 are associated with various skin diseases, including Olmsted syndrome, atopic dermatitis, and rosacea. Here we present the cryo-electron microscopy structures of full-length mouse TRPV3 in the closed apo and agonist-bound open states. The agonist binds three allosteric sites distal to the pore. Channel opening is accompanied by conformational changes in both the outer pore and the intracellular gate. The gate is formed by the pore-lining S6 helices that undergo local α-to-π helical transitions, elongate, rotate, and splay apart in the open state. In the closed state, the shorter S6 segments are entirely α-helical, expose their nonpolar surfaces to the pore, and hydrophobically seal the ion permeation pathway. These findings further illuminate TRP channel activation and can aid in the design of drugs for the treatment of inflammatory skin conditions, itch, and pain.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"805-813"},"PeriodicalIF":16.8,"publicationDate":"2018-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45165464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Integrin alpha-v beta-8 in complex with the Fabs 8B8 and 68","authors":"A. Cormier, M. Campbell, S. Nishimura, Y. Cheng","doi":"10.2210/pdb6djp/pdb","DOIUrl":"https://doi.org/10.2210/pdb6djp/pdb","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"1 1","pages":""},"PeriodicalIF":16.8,"publicationDate":"2018-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68198040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ahmed-Noor A. Agip, J. N. Blaza, H. R. Bridges, C. Viscomi, S. Rawson, S. Muench, J. Hirst
Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recent cryo-EM analyses have produced near-complete models of all 45 subunits in the bovine, ovine and porcine complexes and have identified two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-A structure of complex I from mouse heart mitochondria, a biomedically relevant model system, in the 'active' state. We reveal a nucleotide bound in subunit NDUFA10, a nucleoside kinase homolog, and define mechanistically critical elements in the mammalian enzyme. By comparisons with a 3.9-A structure of the 'deactive' state and with known bacterial structures, we identify differences in helical geometry in the membrane domain that occur upon activation or that alter the positions of catalytically important charged residues. Our results demonstrate the capability of cryo-EM analyses to challenge and develop mechanistic models for mammalian complex I.
{"title":"Mouse mitochondrial complex I in the deactive state","authors":"Ahmed-Noor A. Agip, J. N. Blaza, H. R. Bridges, C. Viscomi, S. Rawson, S. Muench, J. Hirst","doi":"10.2210/PDB6G72/PDB","DOIUrl":"https://doi.org/10.2210/PDB6G72/PDB","url":null,"abstract":"Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recent cryo-EM analyses have produced near-complete models of all 45 subunits in the bovine, ovine and porcine complexes and have identified two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-A structure of complex I from mouse heart mitochondria, a biomedically relevant model system, in the 'active' state. We reveal a nucleotide bound in subunit NDUFA10, a nucleoside kinase homolog, and define mechanistically critical elements in the mammalian enzyme. By comparisons with a 3.9-A structure of the 'deactive' state and with known bacterial structures, we identify differences in helical geometry in the membrane domain that occur upon activation or that alter the positions of catalytically important charged residues. Our results demonstrate the capability of cryo-EM analyses to challenge and develop mechanistic models for mammalian complex I.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"548-556"},"PeriodicalIF":16.8,"publicationDate":"2018-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46272166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transient receptor potential vanilloid (TRPV) channels are activated by ligands and heat and are involved in various physiological processes. In contrast to the architecturally related voltage-gated cation channels, TRPV1 and TRPV2 subtypes possess another activation gate at the selectivity filter that can open widely enough to permeate large organic cations. Despite recent structural advances, the mechanism of selectivity filter gating and permeation for both metal ions and large molecules by TRPV1 or TRPV2 is not well known. Here, we determined two crystal structures of rabbit TRPV2 in its Ca2+-bound and resiniferatoxin (RTx)- and Ca2+-bound forms, to 3.9 A and 3.1 A, respectively. Notably, our structures show that RTx binding leads to two-fold symmetric opening of the selectivity filter of TRPV2 that is wide enough for large organic cation permeation. Combined with functional characterizations, our studies reveal a structural basis for permeation of Ca2+ and large organic cations in TRPV2.
{"title":"Conformational plasticity in the selectivity filter of the TRPV2 ion channel.","authors":"L. Zubcevic, S. Le, Huanghe Yang, Seok-Yong Lee","doi":"10.2210/PDB6BWJ/PDB","DOIUrl":"https://doi.org/10.2210/PDB6BWJ/PDB","url":null,"abstract":"Transient receptor potential vanilloid (TRPV) channels are activated by ligands and heat and are involved in various physiological processes. In contrast to the architecturally related voltage-gated cation channels, TRPV1 and TRPV2 subtypes possess another activation gate at the selectivity filter that can open widely enough to permeate large organic cations. Despite recent structural advances, the mechanism of selectivity filter gating and permeation for both metal ions and large molecules by TRPV1 or TRPV2 is not well known. Here, we determined two crystal structures of rabbit TRPV2 in its Ca2+-bound and resiniferatoxin (RTx)- and Ca2+-bound forms, to 3.9 A and 3.1 A, respectively. Notably, our structures show that RTx binding leads to two-fold symmetric opening of the selectivity filter of TRPV2 that is wide enough for large organic cation permeation. Combined with functional characterizations, our studies reveal a structural basis for permeation of Ca2+ and large organic cations in TRPV2.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"405-415"},"PeriodicalIF":16.8,"publicationDate":"2018-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46376461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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