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5zbz

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Crystal structure of the DEAD domain of Human eIF4A with sanguinarine

Structural highlights

5zbz is a 1 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:	X-ray diffraction, Resolution 1.3086026Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IF4A1_HUMAN ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and is required for mRNA binding to ribosome. In the current model of translation initiation, eIF4A unwinds RNA secondary structures in the 5'-UTR of mRNAs which is necessary to allow efficient binding of the small ribosomal subunit, and subsequent scanning for the initiator codon.^[1] ^[2]

Publication Abstract from PubMed

DEAD-box ATP-dependent helicases (DEAH/D) are a family of conserved genes predominantly involved in gene expression regulation and RNA processing. As its prototype, eIF4AI is an essential component of the protein translation initiation complex. Utilizing a screening system based on wild-type eIF4AI and its L243G mutant with a changed linker domain, we discovered an eIF4AI inhibitor, sanguinarine (SAN) and used it to study the catalytic mechanism of eIF4AI. Herein, we describe the crystal structure of the eIF4AI-inhibitor complex and demonstrate that the binding site displays certain specificity, which can provide the basis for drug design to target eIF4AI. We report that except for competitive inhibition SAN's possible mechanism of action involves interference with eIF4AI catalytic cycling process by hindering the formation of the closed conformation of eIF4AI. In addition, our results highlight a new targetable site on eIF4AI and confirm eIF4AI as a viable pharmacological target.

Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling.,Jiang C, Tang Y, Ding L, Tan R, Li X, Lu J, Jiang J, Cui Z, Tang Z, Li W, Cao Z, Schneider-Poetsch T, Jiang W, Luo C, Ding Y, Liu J, Dang Y Cell Chem Biol. 2019 Oct 17;26(10):1417-1426.e5. doi:, 10.1016/j.chembiol.2019.07.010. Epub 2019 Aug 8. PMID:31402318^[3]

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

References

↑ Loh PG, Yang HS, Walsh MA, Wang Q, Wang X, Cheng Z, Liu D, Song H. Structural basis for translational inhibition by the tumour suppressor Pdcd4. EMBO J. 2009 Feb 4;28(3):274-85. Epub 2009 Jan 15. PMID:19153607 doi:10.1038/emboj.2008.278
↑ Chang JH, Cho YH, Sohn SY, Choi JM, Kim A, Kim YC, Jang SK, Cho Y. Crystal structure of the eIF4A-PDCD4 complex. Proc Natl Acad Sci U S A. 2009 Feb 9. PMID:19204291
↑ Jiang C, Tang Y, Ding L, Tan R, Li X, Lu J, Jiang J, Cui Z, Tang Z, Li W, Cao Z, Schneider-Poetsch T, Jiang W, Luo C, Ding Y, Liu J, Dang Y. Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling. Cell Chem Biol. 2019 Oct 17;26(10):1417-1426.e5. doi:, 10.1016/j.chembiol.2019.07.010. Epub 2019 Aug 8. PMID:31402318 doi:http://dx.doi.org/10.1016/j.chembiol.2019.07.010