Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network

被引：0

作者：

Kleist, Andrew B. ^{[1
,2
,3
,17
]}

Szpakowska, Martyna ^{[4
]}

Talbot, Lindsay J. ^{[5
,6
]}

Slodkowicz, Greg ^{[3
]}

Malinverni, Duccio ^{[3
,7
]}

Thomas, Monica A. ^{[1
,2
]}

Crawford, Kyler S. ^{[1
,2
]}

Mcgrail, Daniel J. ^{[8
]}

Dishman, Acacia F. ^{[1
,2
]}

Wedemeyer, Michael J. ^{[1
,2
]}

Sluter, Madison ^{[7
]}

Yi, S. Stephen ^{[9
,10
]}

Sahni, Nidhi ^{[11
,12
,13
]}

Peterson, Francis C. ^{[1
,2
,14
,15
,16
]}

Chevigne, Andy ^{[4
]}

Volkman, Brian F. ^{[1
,2
,14
,15
,16
]}

Babu, M. Madan ^{[2
,3
,7
]}

机构：

[1] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA

[2] Med Coll Wisconsin, Med Scientist Training Program, Milwaukee, WI 53226 USA

[3] MRC Lab Mol Biol, Cambridge, England

[4] Luxembourg Inst Hlth, Dept Infect & Immun, Immuno Pharmacol & Interact, Esch Sur Alzette, Luxembourg

[5] St Jude Childrens Res Hosp, Dept Bone Marrow Transplantat & Cellular Therapy, Memphis, TN USA

[6] St Jude Childrens Res Hosp, Dept Surg, Memphis, TN USA

[7] St Jude Childrens Res Hosp, Ctr Excellence Data Driven Discovery, Dept Struct Biol, Memphis, TN 38105 USA

[8] Univ Texas MD Anderson Canc Ctr Houston, Dept Syst Biol, Houston, TX 77054 USA

[9] Univ Texas Austin, Dell Med Sch, Dept Oncol, Austin, TX USA

[10] Univ Texas Austin, Univ Dept Biomed Engn 10, Cockrell Sch Engn, Dept Oncol, Austin, TX USA

[11] Univ Texas MD Anderson Canc Ctr Houston, Dept Bioinformat & Computat Biol, Houston, TX USA

[12] Baylor Coll Med, Program Quantitat & Computat Biosci, Houston, TX USA

[13] Univ Texas MD Anderson Canc Ctr Houston, Dept Epigenet & Mol Carcinogenesis, Houston, TX USA

[14] Prot Foundry LLC, W Allis, WI 53214 USA

[15] Med Coll Wisconsin, Program Chem Biol, Milwaukee, WI 53226 USA

[16] Med Coll Wisconsin, Mellowes Ctr Genom Sci & Precis Med, Milwaukee, WI 53226 USA

[17] St Jude Childrens Res Hosp, Ctr Excellence Data Driven Discovery, Dept Struct Biol, Memphis, TN 38105 USA

来源：

CELL | 2025年 / 188卷 / 13期

基金：

瑞士国家科学基金会; 英国医学研究理事会;

关键词：

MULTIPLE SEQUENCE ALIGNMENT; RECEPTOR CXCR4; PEPTIDE MOTIFS; SMALL-MOLECULE; CUTTING EDGE; IMMUNE CELLS; R-PACKAGE; PROTEIN; ACTIVATION; INTERFACE;

D O I：

10.1016/j.cell.2025.03.046

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In humans, selective and promiscuous interactions between 46 secreted chemokine ligands and 23 cell surface chemokine receptors of the G-protein-coupled receptor (GPCR) family form a complex network to coordinate cell migration. While chemokines and their GPCRs each share common structural scaffolds, the molecular principles driving selectivity and promiscuity remain elusive. Here, we identify conserved, semi-conserved, and variable determinants (i.e., recognition elements) that are encoded and decoded by chemokines and their receptors to mediate interactions. Selectivity and promiscuity emerge from an ensemble of generalized ("public/conserved") and specific ("private/variable") determinants distributed among structured and unstructured protein regions, with ligands and receptors recognizing these determinants combinatorially. We employ these principles to engineer a viral chemokine with altered GPCR coupling preferences and provide a web resource to facilitate sequence-structure-function studies and protein design efforts for developing immuno-therapeutics and cell therapies.

引用

页码：3603 / 3622.e27

页数：48

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