9hgp | pdb_00009hgp
Human Carbonic Anhydrase II in complex with a synthetic aromatic oligoamide foldamer
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 PubMedThe starting point of this study is the solid state structure of a complex between human carbonic anhydrase II (HCAII) and a helically folded tetradecaamide aromatic foldamer with a nanomolar HCAII ligand appended at the N terminus of the helix. In this complex, the foldamer is achiral but its handedness is biased by diastereoselective interaction with the protein. Computational analysis of the HCAII surface and inspection of the initial solid state structure led to the suggestion of main chain and side chain modifications of the foldamer helix that would result in an extension of the foldamer protein interface as well as in absolute helix handedness control. Molecular dynamics simulations validated several of these suggested modifications as potentially resulting in favorable foldamer-protein contacts. Five new Fmoc-protected amino acid building blocks bearing new biogenic-like side chains were synthesized. Nine new tetradecaamide sequences with or without the appended HCAII ligand were synthesized on solid phase and purified by RP-HPLC. The solid state structures of four of these sequences in complex with HCAII were obtained and validated the main design principles: (i) side chains can be predictably introduced at precise positions of the foldamer surface to create new contacts with the protein; (ii) side chains modifications do not alter main chain behavior and can be implemented independent from each other; (iii) some main chain units derived from quinoline-, pyridine-, or benzene-based delta-amino acids are largely interchangeable without altering the overall helix curvature in the context of a complex with a protein. An assessment of the K (D) values required the adaptation of an existing fluorescence competition assay and suggested that the side chain and main chain modifications introduced in the new sequences did not result in significant improvement of the affinity of the foldamers to HCA. Structure-based design of an aromatic helical foldamer-protein interface.,Wang L, Douat C, Sigl J, Sai Reddy P, Fischer L, d'Estaintot BL, Liu Z, Pophristic V, Yang Y, Zhang Y, Huc I Chem Sci. 2025 Jun 2;16(27):12385-12396. doi: 10.1039/d5sc01826a. eCollection , 2025 Jul 10. PMID:40510324[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
