Figure 3.

Interactions inside the renin active cleft. A, renin residues are shown as gray, and the AGT peptide is in magenta. Asp³⁸ in renin is hydrogen-bonded to the carbonyl oxygen of the scissile bond and a water (W1) that is also within hydrogen-bond range to the other mutated aspartic acid (Ala²²⁶). The conserved hydrogen bond network Trp⁴⁵-Tyr⁸³-water (W2)-Ser⁴¹-Asp³⁸ is present. B, His⁹ in AGT is hydrogen-bonded to Ser²³³. His⁹ also connects to His¹³ through a bridging water (W3). Ser⁸⁴ in the N-flap forms a hydrogen bond with a water (W4), which connects to the carbonyl oxygen of His⁹. C, binding subsites in the renin active cleft. Subsite S3 (Pro¹¹⁸, Phe¹¹⁹, Leu¹²¹, Ala¹²², and Phe¹²⁴ of renin) accommodates Phe⁸; S1 (Phe¹¹⁹, Phe¹²⁴, Val¹²⁷, Val³⁶, and Tyr⁸³) accommodates Leu¹⁰; S1′ (Leu²²⁴ and Ile³⁰⁵) accommodates Val¹¹; and S2′ (Ile¹³⁷, Leu⁸¹, and Tyr⁸³) accommodates Ile¹². The N-flap of renin is shown as yellow, and the C-flap is in purple. D, the N-flap of renin (yellow) in the AGT–renin complex adopts an “open” position with a movement of 4.8 Å compared with its conformation in the unbound renin (cyan, PDB code 1BBS). There is no such conformational change when a decapeptide substrate (corresponding to residues 4–14 of rat AGT) is bound to mouse submaxillary renin (pink; PDB entry 1SMR). The N-terminal residues 1–10 of the AGT peptide are in magenta and the following residues 11–15 and the glycan are shown as green.