27jo | pdb_000027jo

Crystal structure of the mature form of human ASPRV1 bound to indinavir

spinqualitylabelsall models 27jo, resolution 2.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 27jo is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.08Å Ligands: MK1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease APRV1_HUMAN Lamellar ichthyosis. The disease is caused by variants affecting the gene represented in this entry. Function APRV1_HUMAN Protease responsible for filaggrin processing, essential for the maintenance of a proper epidermis organization. Publication Abstract from PubMed The establishment of the epidermal barrier is essential for terrestrial vertebrate survival. Retroviral-like aspartic protease 1 (ASPRV1), also known as skin aspartic protease (SASPase), plays a central role in this process by facilitating the initial cleavage of profilaggrin into filaggrin monomers, which is vital for skin hydration and barrier integrity. Mutations disrupting this activity are linked to hereditary skin disorders. Evolutionarily, ASPRV1 originated from the domestication of an ancient retroviral sequence and comprises a Gag-like domain and a C-terminal protease domain. While it shares structural similarity with HIV-1 protease (HIV-1 PR), the molecular basis for its unique enzymatic properties and substrate specificity remains unclear. Here, we present the biochemical characterization and crystal structures of mature human ASPRV1 (ASPRV1-14) in multiple states, including wild-type, catalytically inactive mutants bound to self-cleavage and filaggrin peptides, and a complex with the HIV-1 PR inhibitor indinavir. Our results demonstrate that ASPRV1-14 exhibits an ionic strength-dependent monomer-dimer equilibrium, shifting from a low-activity monomer at low ionic strength to a high-activity dimer at high ionic strength. Structural analysis reveals that ASPRV1-14 possesses distinctly hydrophobic S2/S2' pockets, dictating a strict requirement for hydrophobic residues at the P2/P2' positions of substrates and explaining its resistance to most HIV-1 PR inhibitors, except indinavir. Furthermore, analysis of disease-associated mutations indicates two main pathogenic mechanisms: disrupting the S2/S2' pocket ( e. g., V243A) or interfering with the self-cleavage maturation process ( e. g., I186T, K199E, R311C/P, and P314T). Collectively, these findings provide a comprehensive molecular framework for understanding the roles of ASPRV1 in epidermal homeostasis and the pathogenesis of skin diseases, offering insights for future therapeutic development. Structure and enzymatic properties of human retroviral-like aspartic protease 1 and functional roles of disease-associated mutations.,Feng X, Chen Z, Lan C, Ding J Acta Biochim Biophys Sin (Shanghai). 2026 Aug 11. doi: 10.3724/abbs.2026141. PMID:42593882 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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