PDBsum entry 4n4w

Membrane protein, transport protein

PDB id: 4n4w

Contents

Protein chain

457 a.a.

Ligands

NAG-NAG-BMA-MAN

SNT

OLC ×2

PEG

PG4

Metals

_ZN ×2

Waters ×8

PDB id:

4n4w

Name:

Membrane protein, transport protein

Title:

Structure of the human smoothened receptor in complex with sant-1.

Structure:

Cytochrome b(562),smoothened homolog. Chain: a. Fragment: residues 190-555. Synonym: smo,protein gx. Engineered: yes. Mutation: yes

Source:

Shigella flexneri 5 str. 8401, homo sapiens. Human. Organism_taxid: 373384, 9606. Strain: 8401. Gene: cybc, sfv_4255, smo, smoh. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.80Å R-factor: 0.207 R-free: 0.253

Authors:

C.Wang,H.Wu,G.W.Han,V.Cherezov,R.C.Stevens,Gpcr Network (Gpcr)

Key ref:

C.Wang et al. (2014). Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun, 5, 4355. PubMed id: 25008467 DOI: 10.1038/ncomms5355

Date:

08-Oct-13 Release date: 22-Jan-14

Protein chain

Q0SXH8  (Q0SXH8_SHIF8) -  Soluble cytochrome b562 from Shigella flexneri serotype 5b (strain 8401)

Seq: 128 a.a.

Struc: 457 a.a.*

Protein chain

Q99835  (SMO_HUMAN) -  Protein smoothened from Homo sapiens

Seq: 787 a.a.

Struc: 457 a.a.*

* PDB and UniProt seqs differ at 107 residue positions (black crosses)

DOI no: 10.1038/ncomms5355

Nat Commun 5:4355 (2014)

PubMed id: 25008467

Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs.

C.Wang, H.Wu, T.Evron, E.Vardy, G.W.Han, X.P.Huang, S.J.Hufeisen, T.J.Mangano, D.J.Urban, V.Katritch, V.Cherezov, M.G.Caron, B.L.Roth, R.C.Stevens.

ABSTRACT

The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6-2.8 Å resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D473(6.54f) elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules.