EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants.
ジャーナル・号・ページ	Sci Adv, Vol. 9, Issue 29, Page eadg5953, Year 2023
掲載日	2023年7月21日
著者	Min Li / Dario Oliveira Passos / Zelin Shan / Steven J Smith / Qinfang Sun / Avik Biswas / Indrani Choudhuri / Timothy S Strutzenberg / Allan Haldane / Nanjie Deng / Zhaoyang Li / Xue Zhi Zhao / Lorenzo Briganti / Mamuka Kvaratskhelia / Terrence R Burke / Ronald M Levy / Stephen H Hughes / Robert Craigie / Dmitry Lyumkis /
PubMed 要旨	HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), ...HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in the clinic. Resistance to even the best INSTIs is a problem, and the mechanisms of resistance are poorly understood. Here, we analyze combinations of the mutations E138K, G140A/S, and Q148H/K/R, which confer resistance to INSTIs. The investigational drug 4d more effectively inhibited the mutants compared with the approved drug Dolutegravir (DTG). We present 11 new cryo-EM structures of drug-resistant HIV-1 intasomes bound to DTG or 4d, with better than 3-Å resolution. These structures, complemented with free energy simulations, virology, and enzymology, explain the mechanisms of DTG resistance involving E138K + G140A/S + Q148H/K/R and show why 4d maintains potency better than DTG. These data establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase.
リンク	Sci Adv / PubMed:37478179 / PubMed Central
手法	EM (単粒子)
解像度	2.2 - 3.0 Å
構造データ	29307 8fn7 EMDB-29307, PDB-8fn7: Structure of WT HIV-1 intasome bound to Dolutegravir 手法: EM (単粒子) / 解像度: 2.8 Å 29309 8fnd EMDB-29309, PDB-8fnd: Structure of E138K HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 3.0 Å 29312 8fng EMDB-29312, PDB-8fng: Structure of G140A HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 2.2 Å 29313 8fnh EMDB-29313, PDB-8fnh: Structure of Q148K HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 2.5 Å 29315 8fnj EMDB-29315, PDB-8fnj: Structure of E138K/G140A HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 2.4 Å 29317 8fnl EMDB-29317, PDB-8fnl: Structure of E138K/Q148K HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 2.8 Å 29318 8fnm EMDB-29318, PDB-8fnm: Structure of G140A/Q148K HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 2.8 Å 29319 8fnn EMDB-29319, PDB-8fnn: Structure of E138K/G140A/Q148K HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 2.7 Å 29320 8fno EMDB-29320, PDB-8fno: Structure of E138K/G140A/Q148R HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 2.46 Å 29321 8fnp EMDB-29321, PDB-8fnp: Structure of E138K/G140S/Q148H HIV-1 intasome with Dolutegravir bound 手法: EM (単粒子) / 解像度: 2.2 Å 29322 8fnq EMDB-29322, PDB-8fnq: Structure of E138K/G140A/Q148K HIV-1 intasome with 4d bound 手法: EM (単粒子) / 解像度: 2.8 Å
化合物	ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-ZN: Unknown entry ChemComp-DLU: (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide / ドルテグラビル / 薬剤, 抗レトロウイルス剤YM ChemComp-HOH: WATER ChemComp-OZ1*: 4-amino-N-[(2,4-difluorophenyl)methyl]-1-hydroxy-6-(6-hydroxyhexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide
由来	human immunodeficiency virus 1 (ヒト免疫不全ウイルス) human immunodeficiency virus (ヒト免疫不全ウイルス) homo sapiens (ヒト)
キーワード	VIRAL PROTEIN/DNA/INHIBITOR / Integrase / Nucleoprotein complex / Inhibitor / Drug resistance / VIRAL PROTEIN-DNA-INHIBITOR complex