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TitleHelical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 6178, Year 2022
Publish dateOct 19, 2022
AuthorsCharles Bayly-Jones / Christopher J Lupton / Claudia Fritz / Hariprasad Venugopal / Daniel Ramsbeck / Michael Wermann / Christian Jäger / Alex de Marco / Stephan Schilling / Dagmar Schlenzig / James C Whisstock /
PubMed AbstractThe zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal ...The zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal tissue homeostasis meprin α performs key roles in inflammation, immunity, and extracellular matrix remodelling. Dysregulated meprin α is associated with acute kidney injury, sepsis, urinary tract infection, metastatic colorectal carcinoma, and inflammatory bowel disease. Accordingly, meprin α is the target of drug discovery programs. In contrast to meprin β, meprin α is secreted into the extracellular space, whereupon it oligomerises to form giant assemblies and is the largest extracellular protease identified to date (~6 MDa). Here, using cryo-electron microscopy, we determine the high-resolution structure of the zymogen and mature form of meprin α, as well as the structure of the active form in complex with a prototype small molecule inhibitor and human fetuin-B. Our data reveal that meprin α forms a giant, flexible, left-handed helical assembly of roughly 22 nm in diameter. We find that oligomerisation improves proteolytic and thermal stability but does not impact substrate specificity or enzymatic activity. Furthermore, structural comparison with meprin β reveal unique features of the active site of meprin α, and helical assembly more broadly.
External linksNat Commun / PubMed:36261433 / PubMed Central
MethodsEM (single particle) / EM (subtomogram averaging)
Resolution2.4 - 12.7 Å
Structure data

26419

7uab

EMDB-26419: Human pro-meprin alpha (zymogen state)[subparticle localised reconstruction]
PDB-7uab: Human pro-meprin alpha (zymogen state)
Method: EM (single particle) / Resolution: 3.7 Å

26420

7uac

EMDB-26420: Human pro-meprin alpha (zymogen state)[Focused classification and refinement]
PDB-7uac: Human pro-meprin alpha (zymogen state)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-26421: Meprin alpha helix (activated) - full C1 consensus reconstruction
Method: EM (single particle) / Resolution: 3.4 Å

26422

7uae

EMDB-26422: Human meprin alpha (active state)[subparticle localised reconstruction]
PDB-7uae: Human meprin alpha (active state)
Method: EM (single particle) / Resolution: 2.6 Å

26423

7uaf

EMDB-26423, PDB-7uaf:
Human meprin alpha inhibitory complex with compound 10d (N~3~,N~3~-bis[(2H-1,3-benzodioxol-5-yl)methyl]-N-hydroxy-beta-alaninamide)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-26424: Meprin alpha helix in complex with fetuin-B [consensus C1 reconstruction]
Method: EM (single particle) / Resolution: 3.7 Å

26426

7uai

EMDB-26426: Meprin alpha helix in complex with fetuin-B [subparticle localised reconstruction, masked focused refinement]
PDB-7uai: Meprin alpha helix in complex with fetuin-B
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-27689: Sub-tomogram average of pro-meprin alpha supercoiled filament
Method: EM (subtomogram averaging) / Resolution: 12.7 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CA:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-M6X:
N~3~,N~3~-bis[(2H-1,3-benzodioxol-5-yl)methyl]-N-hydroxy-beta-alaninamide

Source
  • homo sapiens (human)
  • Homo sapeins (others)
KeywordsONCOPROTEIN / Metalloprotease / complex / helical / extracellular

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