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Title | CryoEM structure of a therapeutic antibody (favezelimab) bound to human LAG3 determined using a bivalent Fab as fiducial marker. |
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Journal, issue, pages | Structure, Vol. 31, Issue 10, Page 1149-11157.e3, Year 2023 |
Publish date | Oct 5, 2023 |
Authors | Arjun K Mishra / Salman Shahid / Sharanbasappa S Karade / Pragati Agnihotri / Alexander Kolesnikov / S Saif Hasan / Roy A Mariuzza / |
PubMed Abstract | Lymphocyte activation gene 3 protein (LAG3) is an inhibitory receptor that is upregulated on exhausted T cells in tumors. LAG3 is a major target for cancer immunotherapy with many anti-LAG3 ...Lymphocyte activation gene 3 protein (LAG3) is an inhibitory receptor that is upregulated on exhausted T cells in tumors. LAG3 is a major target for cancer immunotherapy with many anti-LAG3 antibodies in clinical trials. However, there is no structural information on the epitopes recognized by these antibodies. We determined the single-particle cryoEM structure of a therapeutic antibody (favezelimab) bound to LAG3 to 3.5 Å resolution, revealing that favezelimab targets the LAG3-binding site for MHC class II, its canonical ligand. The small size of the complex between the conventional (monovalent) Fab of favezelimab and LAG3 (∼100 kDa) presented a challenge for cryoEM. Accordingly, we engineered a bivalent version of Fab favezelimab that doubled the size of the Fab-LAG3 complex and conferred a highly identifiable shape to the complex that facilitated particle selection and orientation for image processing. This study establishes bivalent Fabs as new fiducial markers for cryoEM analysis of small proteins. |
External links | Structure / PubMed:37619561 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.1 - 3.61 Å |
Structure data | EMDB-40646, PDB-8so3: EMDB-40716, PDB-8sr0: PDB-6wkm: PDB-8fwh: |
Chemicals | ChemComp-HOH: ChemComp-EDO: ChemComp-NAG: |
Source |
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Keywords | IMMUNE SYSTEM / Anti Human LAG3 / Fab / inhibitory receptors / IMMUNOSUPPRESSANT / Lymphocyte activation gene 3 protein / favezelimab-LAG3 complex / cryoEM / Single particle reconstruction. |