Volume 11, Issue 9, Pages 1123-1131 (September 2003) The Structure of the Extracellular Region of Human Hepsin Reveals a Serine Protease Domain and a Novel Scavenger Receptor Cysteine-Rich (SRCR) Domain  John R Somoza, Joseph D Ho, Christine Luong, Manjiri Ghate, Paul A Sprengeler, Kyle Mortara, William D Shrader, David Sperandio, Hedy Chan, Mary E McGrath, Bradley A Katz  Structure  Volume 11, Issue 9, Pages 1123-1131 (September 2003) DOI: 10.1016/S0969-2126(03)00148-5

Figure 1 Sequence of Human Hepsin Residues shown in green are proposed to lie in the cytoplasm, and residues shown in orange are proposed to form the transmembrane sequence. Residues shown in blue are extracellular and form part of the construct used for crystallography. Within the extracellular region, there is a mutation, N111A (pink), that was created to remove a potential N-linked glycosylation site. Hepsin is proteolytically cleaved to form the active species; the site of the cleavage is shown with a vertical line. The three arrows point to the residues forming the serine protease's catalytic triad. Structure 2003 11, 1123-1131DOI: (10.1016/S0969-2126(03)00148-5)

Figure 2 Ribbon and Solvent-Accessible Views of Hepsin Showing the Serine Protease Domain and the SRCR Domain (A) Ribbon view; (B) solvent-accessible view; serine protease domain, pink; SRCR domain, cyan. Structure 2003 11, 1123-1131DOI: (10.1016/S0969-2126(03)00148-5)

Figure 3 The Catalytic Domain of Hepsin Is Structurally Homologous to Members of the Chymotrypsin Family of Serine Proteases The serine protease domain of hepsin (red) superimposed on the corresponding domains of tryptase (orange) (1A0L) (Pereira et al., 1998), chymotrypsin (blue) (1AFQ) (Yennawar et al., 1994), uPA (green) (1C5L) (Katz et al., 2000), matriptase (cyan) (1EAX) (Friedrich et al., 2002), and enteropeptidase (yellow) (1EKB) (Lu et al., 1999). The catalytic triad of hepsin is shown in black. Structure 2003 11, 1123-1131DOI: (10.1016/S0969-2126(03)00148-5)

Figure 4 Structure and Associated (2|Fo| − |Fc|), αc Map Showing the Hepsin Active Site with Compound A The electron density map is contoured at 1.0 σ (orange) and 2.4 σ (red). Short hydrogen bonds, cyan; protease-inhibitor and inhibitor-water hydrogen bonds, white; other hydrogen bonds, yellow. The long N2amidine-Oδ2Asp189 hydrogen bond (3.32 Å) is transparent white. Structure 2003 11, 1123-1131DOI: (10.1016/S0969-2126(03)00148-5)

Figure 5 The Noncatalytic Chain of Hepsin Forms an SRCR Domain (A) Stereo figure showing the SRCR domain of hepsin; arrows, β strands; coils, α helices. The strands are labeled A–G according to their positions in the hepsin sequence. (B) Stereo figure showing the SRCR domain of hepsin superimposed on the structure of the SRCR domain of Mac-2 binding protein (Protein Data Bank accession code 1BY2) (Hohenester et al., 1999). The comparison is based on a superposition of 46 pairs of α-carbons from the core of the two proteins (residues 53–57, 62–66, 72–77, 83–103, and 144–152 of hepsin and the corresponding residues of M2BP SRCR). Structure 2003 11, 1123-1131DOI: (10.1016/S0969-2126(03)00148-5)

Figure 6 Model Showing the Proposed Position of the Extracellular Component of Hepsin with Respect to the Plasma Membrane Structure 2003 11, 1123-1131DOI: (10.1016/S0969-2126(03)00148-5)