The water-replenishment pathway including entrance-conduit waters (cyan) and intermediate waters (steel blue). The electron density (2Fo − Fc) is contoured at 1.5σ where not indicated otherwise. (a)–(d) Native CA II structures. WEC3 at 7 and 13 atm and WEC4 at 15 atm are contoured at 1.25σ, and WEC3 at 15 atm is contoured at 1.0σ. (e)–(h) V143I CA II structures. WI′ at 7, 13 and 15 atm and W′EC1 at 15 and 13 atm are contoured at 1.25σ and WI at 0 atm is contoured at 1.0σ. Compared with native CA II, V143I CA II shows significantly perturbed positions for WEC2.