PPM1B utilizes a trinuclear metal architecture for phosphatase activity
2 hydrolysis. In addition to substrate orientation, M3 positions a water molecule to protonate the departing alkoxide, stabilizing the leaving-group. Functionally, M3 substitutes for the arginine clamp in phosphoprotein phosphatases (PPP), revealing that these evolutionarily distinct phosphatase families have converged on the same chemical strategy through fundamentally different catalytic architectures. Together, these findings define a three-metal mechanism in PPM phosphatases and identify the M3 site as a rare and potentially druggable feature for immune and infectious diseases.
Authors
- Aishwarya Prakash (ORCID: https://orcid.org/0000-0003-1441-6237)
- Marlo K. Thompson (ORCID: https://orcid.org/0000-0001-6857-0331)
- Troy Stevens (ORCID: https://orcid.org/0000-0001-9689-929X)
- Thomas C. Rich (ORCID: https://orcid.org/0000-0003-0453-1231)
- Joel Andrews
- A. Deweever (ORCID: https://orcid.org/0000-0002-6168-0076)
- Sarah Sayner (ORCID: https://orcid.org/0000-0002-4587-6634)
- Richard E. Honkanen (ORCID: https://orcid.org/0000-0001-8487-8571)
- R.P. Stevens (ORCID: https://orcid.org/0000-0001-9209-9527)
- Mark R. Swingle
- Viktoriya Solodushko
- Madeline Stone
- Andrzej Wierzbicki
- Edward Alan Salter
- Camryn Hall
- Ji Young Lee
- Mikael F Alexeyev
Institutions
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Organogenesis (United States) (US)
- University of South Alabama (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-27
- DOI
- https://doi.org/10.64898/2026.04.23.720145
- Primary Topic
- ATP Synthase and ATPases Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- American Cancer Society
- University of South Alabama
- National Institutes of Health