View source for 6rtw


==Crystal structure of the Patched-1 (PTCH1) ectodomain in complex with nanobody NB64 and cholesterol-hemisuccinate==
<StructureSection load='6rtw' size='340' side='right'caption='[[6rtw]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6rtw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RTW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RTW 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=6rtw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rtw OCA], [https://pdbe.org/6rtw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rtw RCSB], [https://www.ebi.ac.uk/pdbsum/6rtw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rtw ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PTC1_HUMAN PTC1_HUMAN] Semilobar holoprosencephaly;Monosomy 9q22.3;Alobar holoprosencephaly;Microform holoprosencephaly;Septopreoptic holoprosencephaly;Gorlin syndrome;Lobar holoprosencephaly;Midline interhemispheric variant of holoprosencephaly. The disease may be caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/PTC1_HUMAN PTC1_HUMAN] Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.<ref>PMID:21537345</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Hedgehog (HH) ligands, classical morphogens that pattern embryonic tissues in all animals, are covalently coupled to two lipids-a palmitoyl group at the N terminus and a cholesteroyl group at the C terminus. While the palmitoyl group binds and inactivates Patched 1 (PTCH1), the main receptor for HH ligands, the function of the cholesterol modification has remained mysterious. Using structural and biochemical studies, along with reassessment of previous cryo-electron microscopy structures, we find that the C-terminal cholesterol attached to Sonic hedgehog (Shh) binds the first extracellular domain of PTCH1 and promotes its inactivation, thus triggering HH signaling. Molecular dynamics simulations show that this interaction leads to the closure of a tunnel through PTCH1 that serves as the putative conduit for sterol transport. Thus, Shh inactivates PTCH1 by grasping its extracellular domain with two lipidic pincers, the N-terminal palmitate and the C-terminal cholesterol, which are both inserted into the PTCH1 protein core.

The morphogen Sonic hedgehog inhibits its receptor Patched by a pincer grasp mechanism.,Rudolf AF, Kinnebrew M, Kowatsch C, Ansell TB, El Omari K, Bishop B, Pardon E, Schwab RA, Malinauskas T, Qian M, Duman R, Covey DF, Steyaert J, Wagner A, Sansom MSP, Rohatgi R, Siebold C Nat Chem Biol. 2019 Oct;15(10):975-982. doi: 10.1038/s41589-019-0370-y. Epub 2019, Sep 23. PMID:31548691<ref>PMID:31548691</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6rtw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Protein patched homolog 1|Protein patched homolog 1]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Ansell TB]]
[[Category: Bishop B]]
[[Category: Covey DF]]
[[Category: Duman R]]
[[Category: El Omari K]]
[[Category: Kinnebrew M]]
[[Category: Kowatsch C]]
[[Category: Malinauskas T]]
[[Category: Pardon E]]
[[Category: Qian M]]
[[Category: Rohatgi R]]
[[Category: Rudolf AF]]
[[Category: Sansom MSP]]
[[Category: Schwab RA]]
[[Category: Siebold C]]
[[Category: Steyaert J]]
[[Category: Wagner A]]