View source for 7mhz


==Human Hedgehog acyltransferase (HHAT) in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment==
<StructureSection load='7mhz' size='340' side='right'caption='[[7mhz]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7mhz]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MHZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHZ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AJP:(25R)-2beta,15alpha-dihydroxy-5beta,8alpha,10alpha,14beta,17beta-spirostan-3alpha-yl+beta-D-glucopyranosyl-(1- 3)-beta-D-galactopyranosyl-(1- 2)-[beta-D-xylopyranosyl-(1- 3)]-beta-D-glucopyranosyl-(1- 4)-beta-D-galactopyranoside'>AJP</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PKZ:PALMITOYL-COA'>PKZ</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</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=7mhz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mhz OCA], [https://pdbe.org/7mhz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mhz RCSB], [https://www.ebi.ac.uk/pdbsum/7mhz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mhz ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SHH_HUMAN SHH_HUMAN] Defects in SHH are the cause of microphthalmia isolated with coloboma type 5 (MCOPCB5) [MIM:[https://omim.org/entry/611638 611638]. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure).<ref>PMID:12503095</ref>   Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) [MIM:[https://omim.org/entry/142945 142945]. Holoprosencephaly (HPE) [MIM:[https://omim.org/entry/236100 236100] is the most common structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. Interestingly, up to 30% of obligate carriers of HPE3 gene in autosomal dominant pedigrees are clinically unaffected.<ref>PMID:8896572</ref> <ref>PMID:9302262</ref> <ref>PMID:10441331</ref> <ref>PMID:10556296</ref> <ref>PMID:11479728</ref> <ref>PMID:15107988</ref> <ref>PMID:15221788</ref> <ref>PMID:15942952</ref> <ref>PMID:15942953</ref> <ref>PMID:16282375</ref> <ref>PMID:17001669</ref> <ref>PMID:19603532</ref>   Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) [MIM:[https://omim.org/entry/147250 147250]. SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor.<ref>PMID:11471164</ref> <ref>PMID:15103725</ref>   Defects in SHH are the cause of triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:[https://omim.org/entry/174500 174500]. TPTPS is an autosomal dominant syndrome characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. TPTPS mutations have been mapped to the 7q36 locus in the LMBR1 gene which contains in its intron 5 a long-range cis-regulatory element of SHH expression.<ref>PMID:12837695</ref> 
== Function ==
[https://www.uniprot.org/uniprot/SHH_HUMAN SHH_HUMAN] Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction (By similarity).
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== Publication Abstract from PubMed ==
Hedgehog proteins govern crucial developmental steps in animals and drive certain human cancers. Before they can function as signaling molecules, Hedgehog precursor proteins must undergo amino-terminal palmitoylation by Hedgehog acyltransferase (HHAT). We present cryo-electron microscopy structures of human HHAT in complex with its palmitoyl-coenzyme A substrate and of a product complex with a palmitoylated Hedgehog peptide at resolutions of 2.7 and 3.2 angstroms, respectively. The structures reveal how HHAT overcomes the challenges of bringing together substrates that have different physiochemical properties from opposite sides of the endoplasmic reticulum membrane within a membrane-embedded active site for catalysis. These principles are relevant to related enzymes that catalyze the acylation of Wnt and of the appetite-stimulating hormone ghrelin. The structural and mechanistic insights may advance the development of inhibitors for cancer.

Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT.,Jiang Y, Benz TL, Long SB Science. 2021 Jun 11;372(6547):1215-1219. doi: 10.1126/science.abg4998. PMID:34112694<ref>PMID:34112694</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 7mhz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Jiang Y]]
[[Category: Long SB]]