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-Structure paper
タイトル | Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. |
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ジャーナル・号・ページ | Science, Vol. 370, Issue 6514, Page 360-364, Year 2020 |
掲載日 | 2020年10月16日 |
![]() | Stephanie M Bester / Guochao Wei / Haiyan Zhao / Daniel Adu-Ampratwum / Naseer Iqbal / Valentine V Courouble / Ashwanth C Francis / Arun S Annamalai / Parmit K Singh / Nikoloz Shkriabai / Peter Van Blerkom / James Morrison / Eric M Poeschla / Alan N Engelman / Gregory B Melikyan / Patrick R Griffin / James R Fuchs / Francisco J Asturias / Mamuka Kvaratskhelia / ![]() |
PubMed 要旨 | The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing ...The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies. |
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手法 | EM (らせん対称) / X線回折 |
解像度 | 2.22 - 6.3 Å |
構造データ | EMDB-21423, PDB-6vws: ![]() EMDB-21424: ![]() PDB-6vkv: |
化合物 | ![]() ChemComp-QNG: ![]() ChemComp-IOD: ![]() ChemComp-CL: ![]() ChemComp-HOH: |
由来 |
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![]() | VIRAL PROTEIN / Helical reconstruction / GS-6207 Hexamer HIV / RASTR |