Fig. 5: The 3A7:HTRA1PD(SA) and 1A8: HTRA1PD/(SA) complexes.
From: Cystine-knot peptide inhibitors of HTRA1 bind to a cryptic pocket within the active site region
a The cryptic HTRA1 pocket of the 3A7:HTRA1PD(SA) complex (green sticks) in comparison to the 3B3:HTRA1PD(SA) complex (gray sticks). The 3A7 residue F27, which replaces Y27 of 3B3, is closer to the LoopA-connecting β-strands, allowing the repositioning of the N218 side chain (red arrow, dotted circle), which changes the shape of the pocket. b Cartoon representation of the non-competent HTRA1 active site of 3A7:HTRA1PD(SA) (red) and of 3B3: HTRA1PD(SA) (cyan) in comparison to the non-competent active site of apo-HTRA1 (PDB: 3TJN-chain A) (blue). The entire Loop2 of the 3A7:HTRA1PD(SA) complex is resolved including the residues T348 and A349, which were missing in the 3B3 structure, and Loop2 superimposes perfectly with the non-competent conformation of the apo-HTRA1 reference structure. c The 1A8: HTRA1PD(SA) complex. Shown are the main interactions of 1A8 (chain X) with HTRA1 (chain B; brown) and additional contacts (W34 and F21; orange sticks) with the neighboring HTRA1-chain A (green). The residues of the two HTRA1PD(SA) protomers (surface representation) within 4 Å distance of 1A8 are shown in cyan and magenta, and the main binding loops of 1A8 (cartoon representation) are in salmon (Loop5) and green (Loop2). 1A8 also interacts with the catalytic triad residues H220 and S328A (yellow). Contact residues of 1A8 are labeled in red and those of HTRA1 are in black and in white italics. d The W34 of 1A8 (orange) makes important contacts to Y325 of HTRA1-chain B (brown) and to Q318 and F353 (magenta) of the neighboring protomer HTRA1-chain A. An additional contact to the neighboring protomer comes from F21, which is sandwiched between W34 and W20 (orange), and which contacts K346 of HTRA1-chain A. HTRA1 residues in Fig. 5 are in italics.
