The binding and specificity of chemokine binding proteins, through the lens of experiment and computation

Stark, Lauren E.; Guan, Wenyan; Colvin, Michael E.; LiWang, Patricia J.

doi:10.1016/j.bj.2021.07.004

Cited by 2 publications

(2 citation statements)

References 87 publications

(190 reference statements)

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“…However, the performance of metagenomic sequencing on a selection of arthropods for instance led to a new understanding of the depth and breadth of negative-sense RNA viruses that may cause influenza, Ebola, rabies and more [ 8 ]. In order to maintain virulence, some viruses, as well as parasitic arthropods, have developed a systematic counterstrategy with the help of chemokine binding proteins (CBP) [ 7 , 9 ].…”

Section: Spotlightmentioning

confidence: 99%

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A finger in every pie – The versatility of chemokines

Kattner¹

2022

Biomedical Journal

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Section: Spotlightmentioning

confidence: 99%

“…Understanding CBP better potentially opens the door to the development of anti-inflammatory agents that could for instance incapacitate inflammatory chemokines. Stark and her team furthermore present the opportunity computational simulation offers, allowing a deeper understanding of protein–protein interactions [ 9 ].…”

Section: Spotlightmentioning

confidence: 99%

A finger in every pie – The versatility of chemokines

Kattner¹

2022

Biomedical Journal

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Rational Design of High Affinity Interaction Between CC Chemokine Binding Protein vCCI and CCL17/TARC

Guan,

Stark,

Zhang

et al. 2024

Biochemistry

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The poxvirus-derived protein vCCI (viral CC chemokine inhibitor) binds almost all members of the CC chemokine family with nanomolar affinity, inhibiting their pro-inflammatory actions. Understanding the affinity and specificity of vCCI could lead to new anti-inflammatory therapeutics. CCL17, also known as TARC, is unusual among CC chemokines by having only micromolar binding to vCCI. We have used sequence analysis and molecular simulations to determine the cause of this weak binding, which identified several locations in CCL17 where mutations seemed likely to improve binding to vCCI. Based on the aforementioned analysis, we expressed and tested multiple mutants of CCL17. We found two single point mutants V44K and Q45R that increased binding affinity to vCCI by 2−3-fold and, in combination, further improved affinity by 7-fold. The CCL17 triple mutant G17R/V44K/Q45R yielded a K d of 0.25 ± 0.13 μM, a 68-fold improvement in affinity compared to the complex with wildtype CCL17. A quadruple mutant G17R/V44K/Q45R/R57W showed high affinity (0.59 ± 0.09 μM) compared to the wild type but lower affinity than the triple mutant. This work demonstrates that sequence comparisons and molecular simulations can predict chemokine mutations that increase the level of binding to vCCI, an important first step in developing engineered chemokine inhibitors useful for anti-inflammatory therapy.

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The binding and specificity of chemokine binding proteins, through the lens of experiment and computation

Cited by 2 publications

References 87 publications

A finger in every pie – The versatility of chemokines

A finger in every pie – The versatility of chemokines

Rational Design of High Affinity Interaction Between CC Chemokine Binding Protein vCCI and CCL17/TARC

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