47: Encoding and decoding chemokine-GPCR selectivity

Kleist AB et al., Cell - A data-driven mapping of how 46 human chemokines and 23 GPCRs encode selective and promiscuous interactions. The team defines conserved, semi-conserved and variable determinants, identifies SLiMs in unstructured regions, and uses these rules to rewire a viral chemokine. Key terms: chemokine, GPCR, selectivity, SLiM, protein engineering.

Study Highlights:
The authors integrate sequence alignments, structural complexes, conservation scoring, and functional assays to define conserved, semi-conserved and variable recognition determinants in chemokine-GPCR interfaces. A minimal conserved disulfide-associated hotspot provides generalized recognition while most contacts are variable and concentrated in unstructured N-termini and loops. Short linear motifs (SLiMs) in these unstructured regions encode network-specific selectivity and evolve rapidly. They validate principles by engineering viral vMIP-II mutants with altered receptor preferences and provide a web resource for design.

Conclusion:
Selectivity and promiscuity in the chemokine-GPCR network are hierarchically encoded across conserved and rapidly evolving regions; these principles can guide rational design of chemokines and receptors for therapeutic applications.

Music:
Enjoy the music based on this article at the end of the episode.

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

First author:
Kleist AB

Journal:
Cell

DOI:
10.1016/j.cell.2025.03.046

Reference:
Kleist AB, Szpakowska M, Talbot LJ, et al. Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network. Cell. 2025;188:3603–3622. doi:10.1016/j.cell.2025.03.046

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/encoding-decoding-selectivity-promiscuity-chemokine-gpcr

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of hierarchical encoding of chemokine-GPCR selectivity, generalized/subfamily/network determinants, SLiMs in unstructured regions, negative design, ACKR1 variant effects, viral chemokine reengineering (vMIP-II), and therapeutic implications.
- transcript topics: Hierarchical encoding of chemokine-GPCR selectivity; Public/conserved, semi-conserved, and private/variable determinants; Subfamily-specific sensors distinguishing CC vs CXC; Role of SLiMs in unstructured regions (N-termini and ECL2); Negative design and steric hindrance of non-cognate interactions; ACKR1 Gly42Asp variant and population phenotype links

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Hierarchical encoding of selectivity via generalized (public), subfamily-specific (semi-private), and network-specific (private) determinants
- Generalized recognition is encoded by a minimal set of conserved residues, often near disulfide-rich regions
- Subfamily-specific sensors differentiate CC vs CXC binding modes and involve context-dependent residues
- SLiMs in unstructured regions (N-termini and loops) encode network-specific selectivity
- Negative design features can actively block noncognate chemokine-GPCR interactions (steric hindrance)
- ACKR1 Gly42Asp variant alters binding and immune cell trafficking phenotypes linked to population differences

QC result: Pass.