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Yorodumi- PDB-7mhz: Human Hedgehog acyltransferase (HHAT) in complex with a palmitoyl... -
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-Basic information
Entry | Database: PDB / ID: 7mhz | |||||||||
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Title | Human Hedgehog acyltransferase (HHAT) in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment | |||||||||
Components |
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Keywords | TRANSFERASE/IMMUNE SYSTEM / MBOAT / GOAT / porcupine / acyl transferase / membrane protein / membrane enzyme / ER / palmitoyl-CoA / TRANSFERASE-IMMUNE SYSTEM complex | |||||||||
Function / homology | Function and homology information N-terminal peptidyl-L-cysteine N-palmitoylation / Formation of lateral plate mesoderm / positive regulation of skeletal muscle cell proliferation / right lung development / left lung development / primary prostatic bud elongation / regulation of mesenchymal cell proliferation involved in prostate gland development / mesenchymal smoothened signaling pathway involved in prostate gland development / positive regulation of sclerotome development / tracheoesophageal septum formation ...N-terminal peptidyl-L-cysteine N-palmitoylation / Formation of lateral plate mesoderm / positive regulation of skeletal muscle cell proliferation / right lung development / left lung development / primary prostatic bud elongation / regulation of mesenchymal cell proliferation involved in prostate gland development / mesenchymal smoothened signaling pathway involved in prostate gland development / positive regulation of sclerotome development / tracheoesophageal septum formation / negative regulation of ureter smooth muscle cell differentiation / positive regulation of ureter smooth muscle cell differentiation / negative regulation of kidney smooth muscle cell differentiation / positive regulation of kidney smooth muscle cell differentiation / morphogen activity / regulation of odontogenesis / positive regulation of mesenchymal cell proliferation involved in ureter development / polarity specification of anterior/posterior axis / trunk neural crest cell migration / hindgut morphogenesis / striated muscle tissue development / negative regulation of alpha-beta T cell differentiation / regulation of glial cell proliferation / regulation of prostatic bud formation / O-acyltransferase activity / metanephric mesenchymal cell proliferation involved in metanephros development / formation of anatomical boundary / lung epithelium development / positive regulation of striated muscle cell differentiation / ventral midline development / trachea morphogenesis / cholesterol-protein transferase activity / bud outgrowth involved in lung branching / HHAT G278V doesn't palmitoylate Hh-Np / telencephalon regionalization / epithelial-mesenchymal cell signaling / : / laminin-1 binding / Ligand-receptor interactions / salivary gland cavitation / negative regulation of cholesterol efflux / determination of left/right asymmetry in lateral mesoderm / spinal cord dorsal/ventral patterning / negative regulation of mesenchymal cell apoptotic process / positive regulation of cerebellar granule cell precursor proliferation / cell development / negative regulation of T cell differentiation in thymus / palmitoyltransferase activity / spinal cord motor neuron differentiation / positive regulation of T cell differentiation in thymus / intermediate filament organization / cerebellar granule cell precursor proliferation / mesenchymal cell apoptotic process / embryonic skeletal system development / prostate gland development / establishment of epithelial cell polarity / limb bud formation / lung lobe morphogenesis / Activation of SMO / skeletal muscle fiber differentiation / thalamus development / embryonic foregut morphogenesis / patched binding / embryonic digestive tract morphogenesis / somite development / hindbrain development / negative thymic T cell selection / positive regulation of skeletal muscle tissue development / ectoderm development / epithelial cell proliferation involved in salivary gland morphogenesis / animal organ formation / neuron fate commitment / dorsal/ventral neural tube patterning / stem cell development / mesenchymal cell proliferation involved in lung development / negative regulation of dopaminergic neuron differentiation / skeletal muscle cell proliferation / positive regulation of immature T cell proliferation in thymus / oligodendrocyte development / lymphoid progenitor cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / smooth muscle tissue development / male genitalia development / positive regulation of astrocyte differentiation / regulation of stem cell proliferation / pattern specification process / artery development / self proteolysis / epithelial cell proliferation involved in prostate gland development / branching involved in salivary gland morphogenesis / positive regulation of epithelial cell proliferation involved in prostate gland development / embryonic pattern specification / Release of Hh-Np from the secreting cell / regulation of proteolysis / positive thymic T cell selection / lung-associated mesenchyme development / Formation of axial mesoderm / dopaminergic neuron differentiation / metanephros development / glycosaminoglycan binding Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Long, S.B. / Jiang, Y. | |||||||||
Funding support | United States, 2items
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Citation | Journal: Science / Year: 2021 Title: Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. Authors: Yiyang Jiang / Thomas L Benz / Stephen B Long / Abstract: 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- ...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. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7mhz.cif.gz | 160.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7mhz.ent.gz | 122.7 KB | Display | PDB format |
PDBx/mmJSON format | 7mhz.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/mh/7mhz ftp://data.pdbj.org/pub/pdb/validation_reports/mh/7mhz | HTTPS FTP |
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-Related structure data
Related structure data | 23837MC 7mhyC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Antibody , 2 types, 2 molecules OP
#3: Antibody | Mass: 51307.891 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse) |
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#4: Antibody | Mass: 22868.863 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse) |
-Protein/peptide / Protein , 2 types, 2 molecules BA
#1: Protein/peptide | Mass: 750.848 Da / Num. of mol.: 1 / Fragment: UNP residues 24-31 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15465 |
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#2: Protein | Mass: 57358.742 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: HHAT, MART2, SKI1 / Production host: Homo sapiens (human) References: UniProt: Q5VTY9, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups |
-Non-polymers , 4 types, 15 molecules
#5: Chemical | ChemComp-PLM / | ||
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#6: Chemical | ChemComp-HEM / | ||
#7: Chemical | #8: Chemical | ChemComp-AJP / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: HHAT in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Mus musculus (house mouse) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy |
Image recording | Electron dose: 43.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142121 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 112.57 Å2 | ||||||||||||||||||||||||
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