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Structure paper

TitleStructure, mechanism, and inhibition of Hedgehog acyltransferase.
Journal, issue, pagesMol Cell, Vol. 81, Issue 24, Page 5025-5038.e10, Year 2021
Publish dateDec 16, 2021
AuthorsClaire E Coupland / Sebastian A Andrei / T Bertie Ansell / Loic Carrique / Pramod Kumar / Lea Sefer / Rebekka A Schwab / Eamon F X Byrne / Els Pardon / Jan Steyaert / Anthony I Magee / Thomas Lanyon-Hogg / Mark S P Sansom / Edward W Tate / Christian Siebold /
PubMed AbstractThe Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate ...The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery.
External linksMol Cell / PubMed:34890564 / PubMed Central
MethodsEM (single particle)
Resolution2.61 - 3.59 Å
Structure data

13764

7q1u

EMDB-13764, PDB-7q1u:
Structure of Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to non-hydrolysable palmitoyl-CoA (Composite Map)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-13841:
Focused refinement of Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to non-hydrolysable palmitoyl-CoA
Method: EM (single particle) / Resolution: 2.69 Å

EMDB-13842:
Focused refinement of Hedgehog acyltransferase (HHAT) in complex with megabody 177 - megabody core
Method: EM (single particle) / Resolution: 2.61 Å

13860

7q6z

EMDB-13860, PDB-7q6z:
Structure of Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to IMP-1575
Method: EM (single particle) / Resolution: 3.59 Å

EMDB-14578: Structure of Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to non-hydrolysable palmitoyl-CoA (Consensus Map)
Method: EM (single particle) / Resolution: 3.12 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-HD6:
[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(3~{S})-4-[[3-(2-hexadecylsulfanylethylamino)-3-oxidanylidene-propyl]amino]-2,2-dimethyl-3-oxidanyl-4-oxidanylidene-butyl] hydrogen phosphate

ChemComp-MG:
Unknown entry

ChemComp-PLM:
PALMITIC ACID

ChemComp-9V3:
2-(2-methylpropylamino)-1-[(4R)-4-(6-methylpyridin-2-yl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethanone

Source
  • escherichia coli k-12 (bacteria)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / HHAT / inhibitor / palmitoyl-CoA / co enzyme A / Hedgehog acyl transferase / Sonic Hedgehog / SHH / MBOAT / morphogen / palmitoylation / signalling / endoplasmic reticulum / heme / small molecule binding / drug target

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