6om7

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Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like small molecule with AA and PE tRNAs

6om7, resolution 3.70Å

Structural highlights

6om7 is a 10 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.7Å
Ligands:
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RSSA_HUMAN Required for the assembly and/or stability of the 40S ribosomal subunit. Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits. Also functions as a cell surface receptor for laminin. Plays a role in cell adhesion to the basement membrane and in the consequent activation of signaling transduction pathways. May play a role in cell fate determination and tissue morphogenesis. Acts as a PPP1R16B-dependent substrate of PPP1CA. Also acts as a receptor for several other ligands, including the pathogenic prion protein, viruses, and bacteria.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyl-transfer RNA 3'-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest.

Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule.,Li W, Ward FR, McClure KF, Chang ST, Montabana E, Liras S, Dullea RG, Cate JHD Nat Struct Mol Biol. 2019 Jun;26(6):501-509. doi: 10.1038/s41594-019-0236-8. Epub, 2019 Jun 3. PMID:31160784^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Terranova VP, Rao CN, Kalebic T, Margulies IM, Liotta LA. Laminin receptor on human breast carcinoma cells. Proc Natl Acad Sci U S A. 1983 Jan;80(2):444-8. PMID:6300843
↑ Kim K, Li L, Kozlowski K, Suh HS, Cao W, Ballermann BJ. The protein phosphatase-1 targeting subunit TIMAP regulates LAMR1 phosphorylation. Biochem Biophys Res Commun. 2005 Dec 23;338(3):1327-34. Epub 2005 Oct 25. PMID:16263087 doi:10.1016/j.bbrc.2005.10.089
↑ Kim KJ, Chung JW, Kim KS. 67-kDa laminin receptor promotes internalization of cytotoxic necrotizing factor 1-expressing Escherichia coli K1 into human brain microvascular endothelial cells. J Biol Chem. 2005 Jan 14;280(2):1360-8. Epub 2004 Oct 29. PMID:15516338 doi:M410176200
↑ Li W, Ward FR, McClure KF, Chang ST, Montabana E, Liras S, Dullea RG, Cate JHD. Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule. Nat Struct Mol Biol. 2019 Jun;26(6):501-509. doi: 10.1038/s41594-019-0236-8. Epub, 2019 Jun 3. PMID:31160784 doi:http://dx.doi.org/10.1038/s41594-019-0236-8