# Platelet alphaIIbbeta3 activation and its therapeutic targeting

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $533,504

## Abstract

Abstract
Platelet αIIbβ3 is required for normal hemostasis, but is also a validated drug target because of its essential
role in pathologic thrombosis. αIIbβ3 is normally kept in an inactive bent conformation on circulating platelets,
but rapidly switches to an active (ligand-binding) conformation in response to inside-out signaling. The ligand-
occupied receptor then transmits outside-in signals via the αβ transmembrane (TM) and cytoplasmic domains
that initiate platelet adhesion, a response inadvertently produced by current orthosteric inhibitory drugs, which
has limited their clinical efficacy. The structural basis of bidirectional integrin signaling remains to be clarified.
One model suggests that the ligand-binding site directly faces the plasma membrane in the bent conformation,
with integrin genuextension required for access to ligand. However, the integrin ectodomain/TM tilt has not
been defined experimentally. Further, regulated αβ TM domain association in integrins is driven by the
ectodomain, which may explain some of the differences found in the reported NMR structures of the isolated
αIIbβ3 TM domains. In preliminary studies, we produce a low-resolution cryo-EM structure of full-length αIIbβ3
in an unexpected orientation relative to the membrane, the result of its complex in cis with a tetraspanner,
providing the first experimental definition of an integrin ectodomain/TM tilt, and novel insights into the
structural basis of αIIbβ3 activation. We also develop a water soluble, stable and high affinity orthosteric
inhibitor of αIIbβ3 that is not a partial agonist, and use it in a structure-guided approach to generate like
compounds. We propose to expand on these preliminary data in three specific aims, utilizing multidisciplinary
approaches that include electron cryomicroscopy, tomography, protein crystallography, structure-based drug
design, new peptide synthesis technology and novel murine models of thrombosis.

## Key facts

- **NIH application ID:** 10469477
- **Project number:** 5R01HL141366-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** M. AMIN ARNAOUT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $533,504
- **Award type:** 5
- **Project period:** 2019-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469477

## Citation

> US National Institutes of Health, RePORTER application 10469477, Platelet alphaIIbbeta3 activation and its therapeutic targeting (5R01HL141366-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469477. Licensed CC0.

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