7y2a
Zn-Carbonic Anhydrase II complexed with 3NPA before UV at 90 K
Structural highlights
DiseaseCAH2_HUMAN Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5] FunctionCAH2_HUMAN Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7] Publication Abstract from PubMedWater plays an essential role in enzyme structure, stability, and the substantial rate enhancement of enzyme catalysis. However, direct observations linking enzyme catalysis and active-site water dynamics pose a significant challenge due to experimental difficulties. By integrating an ultraviolet (UV) photolysis technique with temperature-controlled X-ray crystallography, we track the catalytic pathway of carbonic anhydrase II (CAII) at 1.2 A resolution. This approach enables us to construct molecular movies of CAII catalysis, encompassing substrate (CO(2)) binding, conversion from substrate to product (bicarbonate), and product release. In the catalytic pathway, we identify an unexpected configuration in product binding and correlate it with sub-nanosecond rearrangement of active-site water. Based on these experimental observations, we propose a comprehensive mechanism of CAII and describe the detailed structure and dynamics of active-site water in CAII. Our findings suggest that CAII has evolved to utilize the structure and fast dynamics of the active-site waters for its diffusion-limited catalytic efficiency. Fast product release requires active-site water dynamics in carbonic anhydrase.,Kim JK, Lim SW, Jeong H, Lee C, Kim S, Son DW, Kumar R, Andring JT, Lomelino C, Wierman JL, Cohen AE, Shin TJ, Ghim CM, McKenna R, Jo BH, Min D, Choi JM, Kim CU Nat Commun. 2025 May 12;16(1):4404. doi: 10.1038/s41467-025-59645-x. PMID:40355440[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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