{
  "id": 5352962,
  "title": "A conserved cysteine-histidine-glutamate metal site identifies DUF501 (Rv1025), an essential uncharacterised protein family of Mycobacterium tuberculosis, as a candidate metalloenzyme and drug target",
  "url": "https://urgent.news/2026/09/03/a-conserved-cysteine-histidine-glutamate-metal-site-identifies-duf501",
  "topic": "health",
  "section": "Health & Medicine",
  "published": "2026-09-03T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.08.31.746906v1?rss=1"
  },
  "original_language": "en",
  "account": "My research reveals that a significant portion of the Mycobacterium tuberculosis proteome remains uncharacterized. The 155-residue protein Rv1025, belonging to the domain of unknown function DUF501 (Pfam PF04417), is essential and could serve as an unexplored drug target. This protein family, comprising 4,370 proteins and lacking a Gene Ontology term or solved structure, is similarly uncharacterized across all organisms and essential in three Actinobacterial genera. A search using the Foldseek tool against comprehensive structural databases uncovered no significant homolog, suggesting a unique fold. The operon eno-divIC-Rv1025-ppx2 is consistently conserved across the Actinobacteria phylum, although AlphaFold-Multimer could not identify a direct complex between Rv1025 and its neighboring DivIC. Instead, across 8,700 homologous sequences, a nearly invariant Cys113-His115-Glu59 cluster forms a pocket, which aligns with the presence of a divalent metal (Zn, Fe, or Mn) at 2.25-2.47 Å. This metal placement is consistent when mutated, and an independent predictor corroborates the same site. The triad is found in all 1,472 near-complete bacterial sequences in the Pfam alignment, with no non-conservative substitutions among the 2,228 examined sequences. This feature distinguishes bacterial DUF501 from other organisms, positioning it as a potential metal-binding protein and the first functional hypothesis for this family. Its conserved and essential metal pocket is proposed as a promising drug target, warranting experimental validation.",
  "summary": "A substantial fraction of the Mycobacterium tuberculosis proteome remains functionally uncharacterised. Rv1025, a 155-residue protein carrying the domain of unknown function DUF501 (Pfam PF04417), is essential by transposon mutagenesis and vulnerable by CRISPR interference, an attractive but neglected drug target, yet has never been functionally described. The family (4,370 proteins, no Gene…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 2,
    "also_reported_by": [
      {
        "outlet": "bioRxiv",
        "title": "X-ray crystallographic fragment screening reveals novel and conformationally dynamic ligand-binding sites in Mycobacterium tuberculosis FtsZ",
        "url": "https://urgent.news/2026/09/02/x-ray-crystallographic-fragment-screening-reveals-novel-and",
        "published": "2026-09-02T00:00:00.000Z"
      }
    ]
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}