6RTW

Crystal structure of the Patched-1 (PTCH1) ectodomain in complex with nanobody NB64 and cholesterol-hemisuccinate

Summary for 6RTW

• Entry DOI: 10.2210/pdb6rtw/pdb
• Descriptor: Protein patched homolog 1, Llama-derived nanobody NB64, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: ---- hedgehog morphogen receptor, receptor-nanobody complex, cholesterol, palmitate, lipid-protein-modification, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 49332.67

Authors

Rudolf, A.F.,Kowatsch, C.,El Omari, K.,Malinauskas, T.,Kinnebrew, M.,Ansell, T.B.,Bishop, B.,Pardon, E.,Schwab, R.A.,Qian, M.,Duman, R.,Covey, D.F.,Steyaert, J.,Wagner, A.,Sansom, M.S.P.,Rohatgi, R.,Siebold, C. (deposition date: 2019-05-27, release date: 2019-10-02, Last modification date: 2024-01-24)

Primary citation

Rudolf, A.F.,Kinnebrew, M.,Kowatsch, C.,Ansell, T.B.,El Omari, K.,Bishop, B.,Pardon, E.,Schwab, R.A.,Malinauskas, T.,Qian, M.,Duman, R.,Covey, D.F.,Steyaert, J.,Wagner, A.,Sansom, M.S.P.,Rohatgi, R.,Siebold, C.
The morphogen Sonic hedgehog inhibits its receptor Patched by a pincer grasp mechanism.
Nat.Chem.Biol., 15:975-982, 2019

PubMed Abstract: 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.

PubMed: 31548691
DOI: 10.1038/s41589-019-0370-y

Experimental method

X-RAY DIFFRACTION (1.9 Å)