26rw

Crystal structure of the C65A/M94W/M145W/C167A mutant of Human lipocalin-type Prostaglandin D Synthase in complex with 10-O-(3-fluoropropyl)-substituted SN-38

spinqualitylabelsall models 26rw, resolution 1.24Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 26rw is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.24Å Ligands: A1MG3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PTGDS_HUMAN Catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation. Involved in a variety of CNS functions, such as sedation, NREM sleep and PGE2-induced allodynia, and may have an anti-apoptotic role in oligodendrocytes. Binds small non-substrate lipophilic molecules, including biliverdin, bilirubin, retinal, retinoic acid and thyroid hormone, and may act as a scavenger for harmful hydrophopic molecules and as a secretory retinoid and thyroid hormone transporter. Possibly involved in development and maintenance of the blood-brain, blood-retina, blood-aqueous humor and blood-testis barrier. It is likely to play important roles in both maturation and maintenance of the central nervous system and male reproductive system. Publication Abstract from PubMed Drug leakage from delivery vehicles is a major limitation of drug delivery systems (DDSs) for cancer chemotherapy because premature release of loaded drugs reduces therapeutic efficacy and increases off-target toxicity. We previously developed a DDS for the poorly water-soluble anti-cancer drug SN-38 using lipocalin-type prostaglandin D synthase (L-PGDS). To suppress drug leakage, in this study we generated an L-PGDS mutant (M94W-M145W) with enhanced binding affinity for SN-38 by introducing amino acid substitutions into the ligand-binding cavity. Docking simulations identified residues involved in SN-38 recognition, and selected residues were replaced with tryptophan to strengthen ligand binding. The dissociation constant of the M94W-M145W mutant for SN-38 was 2.7 +/- 0.4 muM, approximately 4-fold lower than that of L-PGDS. In addition, 1 mM M94W-M145W enhanced the solubility of SN-38 by approximately 3.3-fold compared with 1 mM L-PGDS. In vitro release assays showed that the SN-38/M94W-M145W complex released SN-38 more slowly than the SN-38/L-PGDS complex. We also determined the crystal structure of the 10-O-(3-fluoropropyl)-substituted SN-38 derivative/M94W-M145W complex. The overall structure of M94W-M145W retained the typical lipocalin fold, indicating that these substitutions do not alter the global protein architecture. Two SN-38 derivative molecules were accommodated within the cavity through hydrogen bonding and hydrophobic interactions, including pi-pi stacking interactions introduced by the substituted tryptophan residues. These findings demonstrate that simple amino acid substitutions in L-PGDS can optimize drug binding, improve solubility, and suppress drug release, thus providing a basis for affinity-driven design of protein-based DDSs. Development of a drug delivery vehicle protein exhibiting high binding affinity and low leakage of the anti-cancer drug SN-38.,Nakatsuji M, Muroya H, Okubo R, Teraoka Y, Yamada M, Nishide K, Yoshida H, Furuta K, Koyama R, Kida T, Doi H, Nishimura S, Inui T Int J Biol Macromol. 2026 Sep 1;381(Pt 2):154313. doi: , 10.1016/j.ijbiomac.2026.154313. PMID:42680028 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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