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Molecular binding mode of PF-232798, a clinical anti-HIV candidate, at chemokine receptor CCR5

Ya Zhu1,2, Yan-long Zhao2,3,4, Jian Li3,5, Hong Liu3,5, Qiang Zhao2,3,5,6, Bei-li Wu2,3,4,6, Zhen-lin Yang3,5
1 hinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
6 Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China
Correspondence to: Bei-li Wu: beiliwu@simm.ac.cn, Zhen-lin Yang: yangzl417@163.com,
DOI: 10.1038/s41401-018-0054-2
Received: 12 April 2018
Accepted: 22 May 2018
Advance online: 25 June 2018

Abstract

The chemokine receptor CCR5 is an important anti-HIV (human immunodeficiency virus) drug target owning to its pivotal role in HIV-1 viral entry as a co-receptor. Here, we present a 2.9 Å resolution crystal structure of CCR5 bound to PF-232798, a second-generation oral CCR5 antagonist currently in phase II clinical trials. PF-232798 and the marketed HIV drug maraviroc share a similar tropane scaffold with different amino (N)- and carboxyl (C)- substituents. Comparison of the CCR5–PF-232798 structure with the previously determined structure of CCR5 in complex with maraviroc reveals different binding modes of the two allosteric antagonists and subsequent conformational changes of the receptor. Our results not only offer insights into the phenomenon that PF-232798 has higher affinity and alternative resistance profile to maraviroc, but also will facilitate the design of new anti-HIV drugs.
Keywords: CCR5; anti-HIV; PF-232798; maraviroc; antagonist; crystal structure

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