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Structural diversity of full-length human αvβ3 integrin revealed by cryo-EM
Cang Wu1, Yuanzhu Gao2, Weiyan Wang3
1School of Life Science, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
Abstract:
Integrins are essential transmembrane receptors that orchestrate cell adhesion, migration, and survival, and have emerged as promising therapeutic targets for cancer, fibrosis, and autoimmune diseases. However, most integrin-targeted drugs have failed in clinical trials due to limited efficacy and unexpected off-target effects, reflecting an incomplete understanding of integrin conformational regulation. Here, we present a series of high-resolution cryo-EM structures of human integrin αvβ3 in both apo and ligand-bound states by collecting a large amount of data. Consequently, we resolved six conformations of integrin in the apo state, five of which were previously uncharacterized, along with five distinct ligand-bound states, thereby revealing a continuum of conformational transitions underlying integrin activation. Notably, CWHM-12 enables the simultaneous coexistence of integrin in closing and opening inhibited states, revealing a mechanism that differs fundamentally from that of conventional RGD peptide-based inhibitors. Then, our study provides a structural framework for understanding integrin activation diversity and lays the foundation for rational design of next-generation inhibitors with improved precision and reduced off-target effects.
Insights
This study reveals diverse integrin conformations using cryo-EM, offering new insights into integrin activation. These findings pave the way for developing more precise cancer and autoimmune disease therapies.
Area of Science:
- Structural Biology
- Molecular Cell Biology
- Drug Discovery
Background:
- Integrins are key cell surface receptors regulating critical cellular processes.
- Current integrin-targeting drugs face challenges in efficacy and specificity.
- Understanding integrin conformational dynamics is crucial for therapeutic development.
Purpose of the Study:
- To elucidate the conformational landscape of human integrin αvβ3.
- To characterize novel integrin conformations in apo and ligand-bound states.
- To provide a structural basis for designing improved integrin inhibitors.
Main Methods:
- High-resolution cryo-electron microscopy (cryo-EM) data collection and analysis.
- Determination of multiple integrin αvβ3 structures.
- Comparative analysis of distinct integrin conformations.
Main Results:
- Resolved six apo and five ligand-bound states of integrin αvβ3, revealing a continuum of activation.
- Identified five previously uncharacterized apo conformations.
- Demonstrated a novel inhibition mechanism of CWHM-12 distinct from RGD peptides.
Conclusions:
- The study provides a comprehensive structural framework for integrin activation diversity.
- Unveiled previously unknown integrin conformations and activation states.
- Lays the groundwork for next-generation integrin inhibitors with enhanced precision and reduced side effects.
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