Biology subjects

McGoldrick, L. L.

Publications and source records attributed to McGoldrick, L. L..

2 recordsLinked to original sources

bioRxiv2024

Structural characterization of two full length γδTCR/CD3 complexes

The T-cell receptor (TCR)/CD3 complex plays an essential role in the immune response and is a key player in cancer immunotherapies. There are two classes of TCR/CD3 complexes, defined by their TCR chain usage ({beta} or {gamma}{delta}). Recently reported structures have revealed the organization of the {beta} TCR/CD3 complex, but similar studies regarding the {gamma}{delta} TCR/CD3 complex have lagged behind. Here, we report cryoelectron microscopy (cryoEM) structural analysis of two full-length {gamma}{delta} TCRs, G115 (V{gamma}9V{delta}2) and 9C2 (V{gamma}5V{delta}1), in complex with CD3 subunits. Our results show that the overall subunit organization of the {gamma}{delta} TCR-CD3 complexes is similar to {beta} TCRs. However, both {gamma}{delta} TCRs display highly mobile extracellular domains (ECDs), unlike {beta} TCRs, which have TCR ECDs that are rigidly coupled to its transmembrane (TM) domains. We corroborate this finding in cells by demonstrating that a {gamma}{delta} T-cell specific antibody can bind a site that would be inaccessible in the more rigid {beta} TCR/CD3 complex. Furthermore, we observed that a V{gamma}5V{delta}1 complex forms a TCR {gamma}5-chain mediated dimeric species whereby two TCR/CD3 complexes are assembled. Collectively, these data shed light on {gamma}{delta} TCR/CD3 complex formation and may aid the design of {gamma}{delta} TCR-based therapies.

biochemistry↗

bioRxiv2024

Structural insights into CXCR4 modulation and oligomerization

Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. CXCR4 also serves as a key target for diseases such as cancer and HIV. Previously reported crystal structures of CXCR4 bound to antagonists revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood, including its activation by CXCL12, as well as its assembly into higher-order oligomers. Here, we use cryoelectron microscopy (cryoEM) to investigate various modes of CXCR4 regulation in the presence and absence of Gi protein. CXCL12 activates CXCR4 by inserting its N-terminus deep into the CXCR4 orthosteric pocket. The binding of FDA-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the 7 transmembrane helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its CDR-H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal, to our knowledge, previously undescribed modes of GPCR oligomerization. Remarkably, CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.

biochemistry↗