Structural basis for human DPP4 receptor recognition by a pangolin MERS-like coronavirus

Mo Yang; Zehou Li; Jing Chen; Yang Li; Ran Xu; Meihua Wang; Ying Xu; Rong Chen; Weiwei Ji; Xiaoxia Li; Jiayu Wei; Zhengrong Zhou; Minjie Ren; Ke Ma; Jiayu Guan; Guoxiang Mo; Peng Zhou; Bo Shu; Jingjing Guo; Yuan Yuan; Zheng-Li Shi; Shuijun Zhang

doi:10.1371/journal.ppat.1012695

Structural basis for human DPP4 receptor recognition by a pangolin MERS-like coronavirus

PLoS Pathog. 2024 Nov 8;20(11):e1012695. doi: 10.1371/journal.ppat.1012695. eCollection 2024 Nov.

Authors

Mo Yang¹, Zehou Li¹, Jing Chen², Yang Li², Ran Xu³, Meihua Wang², Ying Xu¹, Rong Chen⁴, Weiwei Ji¹, Xiaoxia Li¹, Jiayu Wei¹, Zhengrong Zhou¹, Minjie Ren¹, Ke Ma¹, Jiayu Guan¹, Guoxiang Mo¹, Peng Zhou⁵, Bo Shu², Jingjing Guo³, Yuan Yuan⁶, Zheng-Li Shi², Shuijun Zhang¹

Affiliations

¹ College of Life Sciences, Nanjing Agricultural University, Nanjing, China.
² Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
³ Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China.
⁴ Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing, China.
⁵ Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong, China.
⁶ School of Life Sciences, Anhui University, Hefei, Anhui, China.

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) and the pangolin MERS-like coronavirus MjHKU4r-CoV-1 employ dipeptidyl peptidase 4 (DPP4) as an entry receptor. MjHKU4r-CoV-1 could infect transgenic mice expressing human DPP4. To understand the mechanism of MjHKU4r-CoV-1 entry into cells, we determined the crystal structures of the receptor binding domain (RBD) of MjHKU4r-CoV-1 spike protein bound to human DPP4 (hDPP4) and Malayan pangolin DPP4 (MjDPP4), respectively. The overall hDPP4-binding mode of MjHKU4r-CoV-1 RBD is similar to that of MERS-CoV RBD. MjHKU4r-CoV-1 RBD shows higher binding affinity to hDPP4 compared to the bat MERS-like coronavirus Ty-BatCoV-HKU4. Via swapping residues between MjHKU4r-CoV-1 RBD and Ty-BatCoV-HKU4 RBD, we identified critical determinants on MjHKU4r-CoV-1 that are responsible for virus usage of hDPP4. Our study suggests that MjHKU4r-CoV-1 is more adapted to the human receptor compared to the bat HKU4 coronavirus and highlights the potential of virus emergence into the human population.

Copyright: © 2024 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Animals
Coronavirus Infections / metabolism
Coronavirus Infections / virology
Dipeptidyl Peptidase 4* / chemistry
Dipeptidyl Peptidase 4* / metabolism
Humans
Mice
Middle East Respiratory Syndrome Coronavirus* / metabolism
Pangolins* / virology
Protein Binding
Receptors, Virus / chemistry
Receptors, Virus / metabolism
Spike Glycoprotein, Coronavirus* / chemistry
Spike Glycoprotein, Coronavirus* / metabolism
Virus Internalization

Substances

Dipeptidyl Peptidase 4
DPP4 protein, human
Spike Glycoprotein, Coronavirus
Receptors, Virus

Grants and funding

This work was supported by Jiangsu Agriculture Science and Technology Innovation Fund (CX(23)3074 to S.Z.), National Natural Science Foundation of China (32170158 and 32000659 to S.Z.; 32100128 to Y.X.), Natural Science Foundation of Jiangsu Province (BK20240087 and BK20200545 to S.Z.; BK20200553 to Y.X.; BK20241578 to W.J.), Fundamental Research Funds for the Central Universities (KYRC2021007, KJQN202150, XUEKEN 2022002 and KJJQ2024008 to S.Z.; KYQN2022013 to Y.X.), High-level personnel project of Jiangsu Province (JSSCBS20210290 to Y.X.), Guangzhou laboratory (SRPG22-001 to Z.S.), Guangdong Basic and Applied Basic Research Foundation (2020A1515111015 to Y.Y.) and China Postdoctoral Science Foundation (2024M751428 to W.J.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.