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Nature. 2019 Jul;571(7764):284-288. doi: 10.1038/s41586-019-1355-4. Epub 2019 Jul 1.

Smoothened stimulation by membrane sterols drives Hedgehog pathway activity.

Deshpande I1, Liang J1, Hedeen D2,3, Roberts KJ4,5, Zhang Y4, Ha B6,7,8,9, Latorraca NR6,7,8,9,10, Faust B1, Dror RO6,7,8,9,10, Beachy PA4,5,11,12, Myers BR13,14,15, Manglik A16,17.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
2
Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA.
3
Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
4
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
5
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
6
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
8
Department of Computer Science, Stanford University, Stanford, CA, USA.
9
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
10
Biophysics Program, Stanford University, Stanford, CA, USA.
11
Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
12
Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
13
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Benjamin.Myers@hci.utah.edu.
14
Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA. Benjamin.Myers@hci.utah.edu.
15
Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA. Benjamin.Myers@hci.utah.edu.
16
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA. Aashish.Manglik@ucsf.edu.
17
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA. Aashish.Manglik@ucsf.edu.

Abstract

Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration1. Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinoma and paediatric medulloblastoma2. Hedgehog proteins bind to and inhibit the transmembrane cholesterol transporter Patched-1 (PTCH1), which permits activation of the seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood. Here we report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models3-5, a cholesterol molecule that is critical for SMO activation is bound deep within the seven-transmembrane pocket. We propose that the inactivation of PTCH1 by Hedgehog allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. These results-combined with signalling studies and molecular dynamics simulations-delineate the structural basis for PTCH1-SMO regulation, and suggest a strategy for overcoming clinical resistance to SMO inhibitors.

PMID:
31263273
PMCID:
PMC6709672
[Available on 2020-01-01]
DOI:
10.1038/s41586-019-1355-4
[Indexed for MEDLINE]

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