Journal Article

PUBDB-2026-01390

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural mechanism and inhibitor discovery for DhhP, a Borrelia burgdorferi cyclic di-AMP phosphodiesterase with an Fe/Mn bimetallic center

Klima, M. (Corresponding author)Extern*EMBL* ; Dejmek, M. ; Palusova, A. ; Chalupska, D. ; Pachl, P. ; Huskova, A. ; Hranicek, J. ; Chalupsky, K. ; Moos, M. ; Nencka, R. ; Perner, J. ; Boura, E. (Corresponding author)

2026
Elsevier Science London [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.str.2026.01.016

Abstract: Second messenger signaling through cyclic dinucleotides regulates critical processes in pathogenic bacteria. DhhP is a phosphodiesterase that regulates levels of cyclic di-AMP (c-di-AMP), an essential second messenger, in Borrelia. Genetic inhibition of DhhP is lethal to Borrelia both in vitro and within a mammalian host. Here, we present the crystal structure of DhhP, revealing a heterobimetallic active site containing precisely positioned manganese and iron ions. We demonstrate specific binding sites for each metal, challenging the prevailing paradigm of homobimetallic active centers in bacterial c-di-AMP phosphodiesterases. The enzyme forms asymmetric dimers with coordinated open and closed conformations, suggesting an alternating mechanism for substrate processing. Additionally, we identified and characterized a series of small-molecule inhibitors of DhhP and demonstrated their ability to inhibit the growth of B. burgdorferi and disrupt spirochete morphology. These compounds establish proof of concept for specific targeting of bacterial c-di-AMP phosphodiesterases and further research of c-di-AMP roles in bacterial cells.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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