View source for 5nkn


==Crystal structure of an Anticalin-colchicine complex==
<StructureSection load='5nkn' size='340' side='right'caption='[[5nkn]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5nkn]] 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=5NKN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NKN 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]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LOC:N-[(7S)-1,2,3,10-TETRAMETHOXY-9-OXO-6,7-DIHYDRO-5H-BENZO[D]HEPTALEN-7-YL]ETHANAMIDE'>LOC</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=5nkn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nkn OCA], [https://pdbe.org/5nkn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nkn RCSB], [https://www.ebi.ac.uk/pdbsum/5nkn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nkn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NGAL_HUMAN NGAL_HUMAN] Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. Binds iron through association with 2,5-dihydroxybenzoic acid (2,5-DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis. Involved in innate immunity, possibly by sequestrating iron, leading to limit bacterial growth.<ref>PMID:12453413</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Colchicine is a toxic alkaloid prevalent in autumn crocus (Colchicum autumnale) that binds to tubulin and inhibits polymerization of microtubules. Using combinatorial and rational protein design, we have developed an artificial binding protein based on the human lipocalin 2 that binds colchicine with a dissociation constant of 120 pM, i.e. 10 000-fold stronger than tubulin. Crystallographic analysis of the engineered lipocalin, dubbed Colchicalin, revealed major structural changes in the flexible loop region that forms the ligand pocket at one end of the eight-stranded beta-barrel, resulting in a lid-like structure over the deeply buried colchicine. A cis-peptide bond between residues Phe71 and Pro72 in loop #2 constitutes a peculiar feature and allows intimate contact with the tricyclic ligand. Using directed evolution, we achieved an extraordinary dissociation half-life of more than 9 h for the Colchicalin*colchicine complex. Together with the chemical robustness of colchicine and availability of activated derivatives, this also opens applications as a general-purpose affinity reagent, including facile quantification of colchicine in biological samples. Given that engineered lipocalins, also known as Anticalin(R)proteins, represent a class of clinically validated biopharmaceuticals, Colchicalin may offer a therapeutic antidote to scavenge colchicine and reverse its poisoning effect in situations of acute intoxication.

An engineered lipocalin that tightly complexes the plant poison colchicine for use as antidote as well as bioanalytical applications.,Skerra A, Barkovskiy M, Ilyukhina E, Dauner M, Eichinger A Biol Chem. 2018 Dec 1. pii:, /j/bchm.just-accepted/hsz-2018-0342/hsz-2018-0342.xml. doi:, 10.1515/hsz-2018-0342. PMID:30517073<ref>PMID:30517073</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5nkn" style="background-color:#fffaf0;"></div>

==See Also==
*[[Neutrophil gelatinase-associated lipocalin|Neutrophil gelatinase-associated lipocalin]]
*[[Siderocalin 3D structures|Siderocalin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Barkovskiy M]]
[[Category: Eichinger A]]
[[Category: Skerra A]]