View source for 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==
<StructureSection load='26rw' size='340' side='right'caption='[[26rw]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[26rw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=26RW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=26RW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.24&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1MG3:4-ethyl-7-[(1~{Z})-1-[3-(3-fluoranylpropoxy)-6-$l^{2}-azanylidene-cyclohexa-2,4-dien-1-ylidene]propyl]-4-oxidanyl-1,8-dihydropyrano[3,4-f]indolizin-3-one;$l^{1}-oxidane'>A1MG3</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=26rw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=26rw OCA], [https://pdbe.org/26rw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=26rw RCSB], [https://www.ebi.ac.uk/pdbsum/26rw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=26rw ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PTGDS_HUMAN 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.<ref>PMID:9475419</ref> <ref>PMID:20667974</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:42680028</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 26rw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Inui T]]
[[Category: Muroya H]]
[[Category: Nishimura S]]