# Modulation and inhibition of the osteoclast-specific V-ATPase for bone resorption

> **NIH NIH P20** · CLEMSON UNIVERSITY · 2020 · $178,933

## Abstract

SUMMARY
Bone diseases affect over 53 million people in United States. Low bone density and high bone density are two
malfunctions that lead to osteoporosis and osteopetrosis, respectively. The last one is a rare disease affecting
only 1250 adults in USA. Bone resorption relies on the recruitment of the Vacuolar H+-ATPases (V-ATPases)
of osteoclasts for the acidification of the local extracellular environment to dissolve bone minerals. V-ATPases,
membrane proton pumps, are highly conserved from yeast to humans and could serve as an effective
therapeutic approach to reverse V-ATPase malfunction. V-ATPase is a multi-subunit molecular complex,
where inter-subunit interactions are important for its function. Therefore, we hypothesize that by unraveling
the V-ATPase's mechanism of action and identifying potential inhibitor binding sites, we could target bone
resorption related diseases by structure-guided drug design. Using the yeast V-ATPase as a model system, we
will identify the mechanism of action of known V-ATPases inhibitors: bafilomycin and concanamycin and
luteolin. Currently, the mechanism of inhibition of these molecules is largely unknown mainly due to the lack of
structural information of V-ATPase, which hinders de novo drug development efforts. Recently, the atomistic
views of the yeast V-ATPase at three different functional states have been solved. To complement the
published structural information of the yeast V-ATPase, the PI and his team propose to apply a hybrid
approach composed of state-of-the-art fluorescence spectroscopic methods at a single molecular level in
combination with computational modeling to determine inter-subunit interactions in the yeast V-ATPase to
uncover the mechanism of inhibition of the mentioned inhibitors. The long-term goals is to help develop small-
molecules that specifically target osteoclast specific V-ATPase as a direct therapeutic approach against bone
diseases. With a track record in single molecule experiments delineating the structure-function relationship of
large molecular complexes and membrane receptors, the PI and his research team are uniquely positioned to
pursue the following specific aims: (1) Elucidate the interdomain motions between different subunits of the V-
ATPase during the ATP hydrolysis cycle; (2) Determine the binding sites of existing small molecule effector;
and (3) Determine the inhibition mechanism of existing small molecule effectors. The proposed project will use
the computational and simulation COBRE CORE B to build structural models based on a hybrid experimental
and computational approach. In addition, this project will use the microfabrication CORE C to develop custom-
built microfluidic devices for studying the kinetic response of the V-ATPase at a single molecular level.
Successful completion of the research project will support the PI and his team to establish the proof of concept
as they transition into the study of the structure, dynamics and functions of human osteo...

## Key facts

- **NIH application ID:** 10007933
- **Project number:** 5P20GM121342-03
- **Recipient organization:** CLEMSON UNIVERSITY
- **Principal Investigator:** Hugo Sanabria Hernandez
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $178,933
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007933

## Citation

> US National Institutes of Health, RePORTER application 10007933, Modulation and inhibition of the osteoclast-specific V-ATPase for bone resorption (5P20GM121342-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10007933. Licensed CC0.

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