Arun K Shukla
@arshukla.bsky.social
๐ค 11
๐ฅ 3
๐ 1
Professor
reposted by
Arun K Shukla
Biochemical Society
about 1 month ago
We are so proud of all our Biochemical Society 2027 Award winners. Visit our website to find out more about all of the deserving recipients #BiochemAwards ๐งช
https://ow.ly/mZ6O50YIGo8
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This is for you IIT Kanpur! All credit to the amazing students and fellows in our laboratory! They are the real Superstars!
#Win#For#Science
add a skeleton here at some point
about 1 month ago
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reposted by
Arun K Shukla
Biochemical Society
about 1 month ago
Mark your calendars! We will be announcing our outstanding winners of the Biochemical Society 2027 Awards tomorrow! Check back throughout the day as we will be celebrating excellence across all disciplines of the molecular biosciences
#BiochemAwards
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reposted by
Arun K Shukla
cryoEM papers
2 months ago
Molecular basis of promiscuous chemokine-engagement by the Duffy antigen receptor
www.biorxiv.org/content/10.64898/2026.03.09.710718v1
#cryoem
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reposted by
Arun K Shukla
Bloodsucking Parasites
2 months ago
Molecular basis of promiscuous chemokine-engagement by the Duffy antigen receptor bioRxivpreprint
loading . . .
Molecular basis of promiscuous chemokine-engagement by the Duffy antigen receptor
The Duffy blood group antigen, encoded by a seven transmembrane protein known as Duffy Antigen Receptor for Chemokines (DARC), or Atypical Chemokine Receptor 1 (ACKR1), serves as a key receptor for the malarial parasite, Plasmodium vivax, on erythrocytes. DARC exhibits remarkable functional divergence compared to prototypical chemokine receptors and other G protein-coupled receptors (GPCRs) as it does not engage canonical signal-transducers such as G-proteins, GPCR regulatory kinases (GRKs), and {beta}-arrestins. DARC is a highly promiscuous receptor interacting with several homeostatic and inflammatory C-C and C-X-C subtype chemokines, and similar to other chemokine receptors, these interactions are modulated by post-translational tyrosine sulfation in the N-terminus. A single nucleotide polymorphism in DARC leading to Gly42Asp substitution forms the basis for Fya vs. Fyb Duffy blood group antigen classification with differential impact on Plasmodium vivax infection and cancer progression. However, the molecular basis of promiscuous chemokine-binding by DARC and the modulation by receptor sulfation and Fya/Fyb allelic variation remains unclear. Here, we design a sortase-mediated chemical-ligation strategy to generate purified DARC with naturally-occurring tyrosine sulfation at the N-terminus, and determine high-resolution cryo-EM structures in complex with a C-C type chemokine, CCL7, and a C-X-C type chemokine, CXCL8. We observe that similar to CCL7, CXCL8 engages with DARC primarily through the N-terminus of the receptor, which is in stark contrast with the two-site binding mechanism displayed by other chemokine receptors. Interestingly, the E-L-R motif in CXCL8 engages a pseudo-R-D motif in DARC leading to superficial engagement unlike CXCR2, a prototypical chemokine receptor sharing the same agonist. Moreover, tyrosine sulfation and Fyb allelic variation leads to a repositioning of the receptor N-terminus on the core domain of CXCL8, resulting in distinct interaction network imparting greater binding affinity. Taken together, our study presents novel insights into promiscuous chemokine-binding to DARC, tyrosine sulfation-mediated fine-tuning of chemokine engagement, and a generalizable sortase-mediated chemical-ligation platform applicable to other chemokine receptors.
http://dlvr.it/TRQFx0
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reposted by
Arun K Shukla
bioRxiv Biochemistry
2 months ago
Molecular basis of promiscuous chemokine-engagement by the Duffy antigen receptor
https://www.biorxiv.org/content/10.64898/2026.03.09.710718v1
0
1
1
reposted by
Arun K Shukla
bioRxivpreprint
2 months ago
Molecular basis of promiscuous chemokine-engagement by the Duffy antigen receptor
https://www.biorxiv.org/content/10.64898/2026.03.09.710718v1
0
1
1
reposted by
Arun K Shukla
Bloodsucking Parasites
2 months ago
Molecular basis of promiscuous chemokine-engagement by the Duffy antigen receptor bioRxivpreprint
loading . . .
Molecular basis of promiscuous chemokine-engagement by the Duffy antigen receptor
The Duffy blood group antigen, encoded by a seven transmembrane protein known as Duffy Antigen Receptor for Chemokines (DARC), or Atypical Chemokine Receptor 1 (ACKR1), serves as a key receptor for the malarial parasite, Plasmodium vivax, on erythrocytes. DARC exhibits remarkable functional divergence compared to prototypical chemokine receptors and other G protein-coupled receptors (GPCRs) as it does not engage canonical signal-transducers such as G-proteins, GPCR regulatory kinases (GRKs), and {beta}-arrestins. DARC is a highly promiscuous receptor interacting with several homeostatic and inflammatory C-C and C-X-C subtype chemokines, and similar to other chemokine receptors, these interactions are modulated by post-translational tyrosine sulfation in the N-terminus. A single nucleotide polymorphism in DARC leading to Gly42Asp substitution forms the basis for Fya vs. Fyb Duffy blood group antigen classification with differential impact on Plasmodium vivax infection and cancer progression. However, the molecular basis of promiscuous chemokine-binding by DARC and the modulation by receptor sulfation and Fya/Fyb allelic variation remains unclear. Here, we design a sortase-mediated chemical-ligation strategy to generate purified DARC with naturally-occurring tyrosine sulfation at the N-terminus, and determine high-resolution cryo-EM structures in complex with a C-C type chemokine, CCL7, and a C-X-C type chemokine, CXCL8. We observe that similar to CCL7, CXCL8 engages with DARC primarily through the N-terminus of the receptor, which is in stark contrast with the two-site binding mechanism displayed by other chemokine receptors. Interestingly, the E-L-R motif in CXCL8 engages a pseudo-R-D motif in DARC leading to superficial engagement unlike CXCR2, a prototypical chemokine receptor sharing the same agonist. Moreover, tyrosine sulfation and Fyb allelic variation leads to a repositioning of the receptor N-terminus on the core domain of CXCL8, resulting in distinct interaction network imparting greater binding affinity. Taken together, our study presents novel insights into promiscuous chemokine-binding to DARC, tyrosine sulfation-mediated fine-tuning of chemokine engagement, and a generalizable sortase-mediated chemical-ligation platform applicable to other chemokine receptors.
http://dlvr.it/TRRcs7
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1
reposted by
Arun K Shukla
Trends in Biochemical Sciences
about 2 months ago
๐
@arshukla.bsky.social
and
@yaeldavidmsk.bsky.social
, two inspiring members of our Advisory Board, share their reflections and hopes for their fields in our special
#TIBSCelebrates50
series "Perspectives from the Advisory Board". Keep up with the series at ๐
www.cell.com/trends/bioch...
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reposted by
Arun K Shukla
Brett Collins
3 months ago
First speaker of last day of Lorne Proteins. Arun Shukla on the mechanism of arrestin coupling to GPCRs.
@arshukla.bsky.social
@lorneproteins.bsky.social
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reposted by
Arun K Shukla
bioRxiv Biochemistry
7 months ago
Molecular mechanism of naturally-encoded signaling-bias at the complement anaphylatoxin receptors
https://www.biorxiv.org/content/10.1101/2025.11.01.685996v1
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reposted by
Arun K Shukla
bioRxivpreprint
7 months ago
Molecular mechanism of naturally-encoded signaling-bias at the complement anaphylatoxin receptors
https://www.biorxiv.org/content/10.1101/2025.11.01.685996v1
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reposted by
Arun K Shukla
cryoEM papers
7 months ago
Atypical activation and molecular glue-like dimerization mechanism of an intrinsically-biased chemokine receptor
www.biorxiv.org/content/10.1101/2025.10.30.685530v1
#cryoem
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reposted by
Arun K Shukla
bioRxiv Biochemistry
7 months ago
Atypical activation and molecular glue-like dimerization mechanism of an intrinsically-biased chemokine receptor
https://www.biorxiv.org/content/10.1101/2025.10.30.685530v1
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reposted by
Arun K Shukla
bioRxivpreprint
7 months ago
Atypical activation and molecular glue-like dimerization mechanism of an intrinsically-biased chemokine receptor
https://www.biorxiv.org/content/10.1101/2025.10.30.685530v1
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