6qba

==Crystal Structure of Retinol-Binding Protein 4 (RBP4) in complex with non-retinoid ligand A1120 and engineered binding scaffold==

<StructureSection load='6qba' size='340' side='right'caption='[[6qba]], [[Resolution|resolution]] 1.80&Aring;' scene=''>

<table><tr><td colspan='2'>[[6qba]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Saccharolobus_solfataricus Saccharolobus solfataricus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QBA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QBA 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]] 1.8&#8491;</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2T1:2-[({4-[2-(TRIFLUOROMETHYL)PHENYL]PIPERIDIN-1-YL}CARBONYL)AMINO]BENZOIC+ACID'>2T1</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>

== Disease ==

[https://www.uniprot.org/uniprot/RET4_HUMAN RET4_HUMAN] Defects in RBP4 are a cause of retinol-binding protein deficiency (RBP deficiency) [MIM:[https://omim.org/entry/180250 180250]. This condition causes night vision problems. It produces a typical 'fundus xerophthalmicus', featuring a progressed atrophy of the retinal pigment epithelium.

== Function ==

[https://www.uniprot.org/uniprot/RET4_HUMAN RET4_HUMAN] Delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin, this prevents its loss by filtration through the kidney glomeruli.

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== Publication Abstract from PubMed ==

Molecular ON-switches in which a chemical compound induces protein-protein interactions can allow cellular function to be controlled with small molecules. ON-switches based on clinically applicable compounds and human proteins would greatly facilitate their therapeutic use. Here, we developed an ON-switch system in which the human retinol binding protein 4 (hRBP4) of the lipocalin family interacts with engineered hRBP4 binders in a small molecule-dependent manner. Two different protein scaffolds were engineered to bind to hRBP4 when loaded with the orally available small molecule A1120. The crystal structure of an assembled ON-switch shows that the engineered binder specifically recognizes the conformational changes induced by A1120 in two loop regions of hRBP4. We demonstrate that this conformation-specific ON-switch is highly dependent on the presence of A1120, as demonstrated by an approximately 500-fold increase in affinity upon addition of the small molecule drug. Furthermore, the ON-switch successfully regulated the activity of primary human CAR T cells in vitro. We anticipate that lipocalin-based ON-switches have the potential to be broadly applied for the safe pharmacological control of cellular therapeutics.

A conformation-specific ON-switch for controlling CAR T cells with an orally available drug.,Zajc CU, Dobersberger M, Schaffner I, Mlynek G, Puhringer D, Salzer B, Djinovic-Carugo K, Steinberger P, De Sousa Linhares A, Yang NJ, Obinger C, Holter W, Traxlmayr MW, Lehner M Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):14926-14935. doi:, 10.1073/pnas.1911154117. Epub 2020 Jun 17. PMID:32554495<ref>PMID:32554495</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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<div class="pdbe-citations 6qba" style="background-color:#fffaf0;"></div>

== References ==

<references/>

[[Category: Homo sapiens]]

[[Category: Saccharolobus solfataricus]]

[[Category: Puehringer D]]