# Structural Transition of Cellular Integrins and Applications Thereof

> **NIH NIH R01** · VERSITI BLOOD HEALTH, INC. · 2020 · $560,922

## Abstract

SUMMARY - Integrins are α/β heterodimeric cell surface receptors, which, via their ability to bind ligands through
extracellular domains and to recruit a series of effector proteins in proximity to cytoplasmic tails, regulate diverse
biological processes and play critical roles in many human diseases. Normal biological functions of integrins,
such as αIIbβ3-mediated hemostasis, are regulated by a tightly-controlled balance between activated and
deactivated states. Inappropriate activation of αIIbβ3 integrin in platelets causes thrombosis, making αIIbβ3 a
validated anti-thrombotic target. Resting αIIbβ3 assumes a compact bent conformation. Upon activation induced
by proteins binding to either the extracellular or cytoplasmic face, it undergoes a long-range conformational
rearrangement characterized by an extension and opening of the headpiece and separation of the leg domains.
Such conformational activation is required for high-affinity ligand binding and returning it to the resting state, i.e.
deactivation, is important for maintaining appropriate αIIbβ3 function. Although structural studies revealed multiple
static conformations of integrin, representing the inactive, intermediate, and active states, it remains elusive how
the α and β subunits, both of which consist of multiple domains, act in concert to perform the reversible large-
scale structural transitions between the active and inactive states. Little is known about the contribution of cell
membrane in regulating integrin conformational changes. Our recent structural and functional studies of β3 in the
absence of α subunit revealed novel aspects of integrin conformational regulation on the cell surface, suggesting
previously uncharacterized roles of the cell membrane and other elements. We have identified a series of ligand-
competitive inactivating inhibitors, which can displace the activating ligand from αIIbβ3 without inducing
conformational changes. Furthermore, we have adapted the ex vivo production of iPS-derived human platelets
to αIIbβ3 signaling studies. Based on these findings, the Aim 1 of this grant seeks to examine the molecular
mechanism of integrin conformational activation and deactivation and dissect the regulatory functions of the cell
membrane and other undefined factors. Using the inactivating inhibitors as tool compounds, we will define the
intrinsic structure features that govern integrin conformational deactivation utilizing a combination of novel
crystallographic, biochemical and biophysical approaches. The acquired structural information will be used to
explore novel concepts of modulating integrin function by targeting conformational changes using small-molecule
and antibody regulators. The second aim will extend our studies on integrin cytoplasmic tails to examining the
composition and dynamics of the supramolecular signaling complex formed intracellularly following agonist- and
ligand-induced αIIbβ3 activation, which will be performed in genetically engineered ...

## Key facts

- **NIH application ID:** 10052843
- **Project number:** 2R01HL131836-05
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** Jieqing Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $560,922
- **Award type:** 2
- **Project period:** 2016-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052843

## Citation

> US National Institutes of Health, RePORTER application 10052843, Structural Transition of Cellular Integrins and Applications Thereof (2R01HL131836-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10052843. Licensed CC0.

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