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Structure paper

TitleAllosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 5222, Year 2022
Publish dateSep 5, 2022
AuthorsStefan Gerhardy / Mark Ultsch / Wanjian Tang / Evan Green / Jeffrey K Holden / Wei Li / Alberto Estevez / Chris Arthur / Irene Tom / Alexis Rohou / Daniel Kirchhofer /
PubMed AbstractThe trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric ...The trimeric serine protease HTRA1 is a genetic risk factor associated with geographic atrophy (GA), a currently untreatable form of age-related macular degeneration. Here, we describe the allosteric inhibition mechanism of HTRA1 by a clinical Fab fragment, currently being evaluated for GA treatment. Using cryo-EM, X-ray crystallography and biochemical assays we identify the exposed LoopA of HTRA1 as the sole Fab epitope, which is approximately 30 Å away from the active site. The cryo-EM structure of the HTRA1:Fab complex in combination with molecular dynamics simulations revealed that Fab binding to LoopA locks HTRA1 in a non-competent conformational state, incapable of supporting catalysis. Moreover, grafting the HTRA1-LoopA epitope onto HTRA2 and HTRA3 transferred the allosteric inhibition mechanism. This suggests a conserved conformational lock mechanism across the HTRA family and a critical role of LoopA for catalysis, which was supported by the reduced activity of HTRA1-3 upon LoopA deletion or perturbation. This study reveals the long-range inhibition mechanism of the clinical Fab and identifies an essential function of the exposed LoopA for activity of HTRA family proteases.
External linksNat Commun / PubMed:36064790 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.8 - 3.4 Å
Structure data

25162

7sjn

EMDB-25162, PDB-7sjn:
HtrA1:Fab15H6.v4 complex
Method: EM (single particle) / Resolution: 3.4 Å

25163

7sjo

EMDB-25163, PDB-7sjo:
HtrA1S328A:Fab15H6.v4 complex
Method: EM (single particle) / Resolution: 3.3 Å

PDB-7sjm:
anti-HtrA1 Fab15H6.v4
Method: X-RAY DIFFRACTION / Resolution: 1.8 Å

PDB-7sjp:
anti-HtrA1 Fab15H6.v4 bound to HtrA1-LoopA peptide
Method: X-RAY DIFFRACTION / Resolution: 2.1 Å

Chemicals

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsIMMUNE SYSTEM / Fab / HYDROLASE/Immune System / HtrA1 / allosteric inhibition / Age-related macular degeneration / Geographic Atrophy / Antibody complex / HYDROLASE / HYDROLASE-Immune System complex / Fab Htra 1 peptide complex

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