SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity

被引：86

作者：

Rosa, Annachiara ^{[1
]}

Pye, Valerie E. ^{[1
]}

Graham, Carl ^{[2
]}

Muir, Luke ^{[3
]}

Seow, Jeffrey ^{[2
]}

Ng, Kevin W. ^{[4
]}

Cook, Nicola J. ^{[1
]}

Rees-Spear, Chloe ^{[3
]}

Parker, Eleanor ^{[5
]}

dos Santos, Mariana Silva ^{[6
]}

Rosadas, Carolina ^{[5
]}

Susana, Alberto ^{[7
]}

Rhys, Hefin ^{[8
]}

Nans, Andrea ^{[9
]}

Masino, Laura ^{[9
]}

Roustan, Chloe ^{[9
]}

Christodoulou, Evangelos ^{[9
]}

Ulferts, Rachel ^{[10
]}

Wrobel, Antoni G. ^{[11
]}

Short, Charlotte-Eve ^{[5
]}

Fertleman, Michael ^{[12
]}

Sanders, Rogier W. ^{[13
,14
]}

Heaney, Judith ^{[15
,16
]}

Spyer, Moira ^{[15
,16
,17
]}

Kjaer, Svend ^{[9
]}

Riddell, Andy ^{[8
]}

Malim, Michael H. ^{[2
]}

Beale, Rupert ^{[10
]}

MacRae, James, I ^{[6
]}

Taylor, Graham P. ^{[5
]}

Nastouli, Eleni ^{[15
,16
,17
]}

van Gils, Marit J. ^{[13
]}

Rosenthal, Peter B. ^{[18
]}

Pizzato, Massimo ^{[7
]}

McClure, Myra O. ^{[5
]}

Tedder, Richard S. ^{[5
]}

Kassiotis, George ^{[4
,5
]}

McCoy, Laura E. ^{[3
]}

Doores, Katie J. ^{[2
]}

Cherepanov, Peter ^{[1
,5
]}

机构：

[1] Francis Crick Inst, Chromatin Struct & Mobile DNA Lab, London, England

[2] Kings Coll London, Sch Immunol & Microbial Sci, Dept Infect Dis, London, England

[3] UCL, Inst Immun & Transplantat, Div Infect & Immun, London, England

[4] Francis Crick Inst, Retroviral Immunol Lab, London, England

[5] Imperial Coll London, Dept Infect Dis, St Marys Campus, London, England

[6] Francis Crick Inst, Metabol Sci Technol Platform, London, England

[7] Univ Trento, Dept Cellular Computat & Integrat Biol, Trento, Italy

[8] Francis Crick Inst, Flow Cytometry Sci & Technol Platform, London, England

[9] Francis Crick Inst, Struct Biol Sci Technol Platform, London, England

[10] Francis Crick Inst, Cell Biol Infect Lab, London, England

[11] Francis Crick Inst, Struct Biol Dis Proc Lab, London, England

[12] Imperial Coll London, Cutrale Perioperat & Ageing Grp, London, England

[13] Univ Amsterdam, Amsterdam Inst Infect & Immun, Dept Med Microbiol, Amsterdam UMC, Amsterdam, Netherlands

[14] Cornell Univ, Weill Med Coll, New York, NY 10021 USA

[15] Univ Coll London Hosp NHS Fdn Trust, Adv Pathogen Diagnost Unit, London, England

[16] Francis Crick Inst, Crick COVID 19 Consortium, London, England

[17] UCL Great Ormond St Inst Child Hlth, Dept Infect Immun & Inflammat, London, England

[18] Francis Crick Inst, Struct Biol Cells & Viruses Lab, London, England

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 22期

基金：

英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

CRYO-EM STRUCTURE; MONOCLONAL-ANTIBODIES; SPIKE; SYSTEM; VALIDATION; MOLPROBITY; EFFICIENT; BINDING; MODELS; PHENIX;

D O I：

10.1126/sciadv.abg7607

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARSCoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.

引用

页数：14

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