9Z0F

Crystal structure of Trastuzumab Fc conjugated to Linker-Payload

This is a non-PDB format compatible entry.

Summary for 9Z0F

• Entry DOI: 10.2210/pdb9z0f/pdb
• Descriptor: Trastuzumab Fc, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: trastuzumab, adc, fc, igg1, antibody, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 54215.23

Authors

Jaime-Garza, M.,Noland, C.L.,Gabelli, S.B. (deposition date: 2025-10-31, release date: 2025-12-24, Last modification date: 2026-01-14)

Primary citation

Jaime-Garza, M.,Waight, A.,Hudlikar, M.,Eddins, M.J.,Rasti, E.S.,Zaragoza, J.P.T.,Fayadat-Dilman, L.,Chrencik, J.E.,Gabelli, S.B.,Chen, Y.T.,Noland, C.L.
Structural Characterization of Linker Shielding in ADC Site-Specific Conjugates.
Pharmaceutics, 17:-, 2025

PubMed Abstract: : Antibody-Drug Conjugates (ADCs) have rapidly evolved from early, rudimentary conjugates to highly targeted and precisely engineered molecules. Despite notable clinical successes, ADCs continue to face significant challenges, including aggregation and high hydrophobicity driven by high drug-to-antibody ratios (DARs), premature payload release, dose-limiting toxicities, and suboptimal pharmacokinetics. While site-specific linker-payload conjugation has improved ADC homogeneity and stability, the structural basis of antibody-linker interactions at specific sites remains underexplored. : In this work, we present the crystal structures of trastuzumab Fab and Fc domains site-specifically conjugated with a cleavable linker-payload. : Our findings suggest that pockets within both Fab and Fc regions may interact with and shield the linker portion of the conjugate. : These insights highlight the previously underappreciated potential of structure-based design to drive the optimization of ADC linker chemistry and facilitate the co-design of bespoke linker-payloads tailored to individual antibody conjugation sites.

PubMed: 41471083
DOI: 10.3390/pharmaceutics17121568

Experimental method

X-RAY DIFFRACTION (2.46 Å)