PDBsum entry 5js1

Hydrolase/RNA

PDB id: 5js1

Contents

Protein chain

801 a.a.

DNA/RNA

Ligands

IPH ×2

Metals

_MG

Waters ×52

PDB id:

5js1

Name:

Hydrolase/RNA

Title:

Human argonaute2 bound to an sirna

Structure:

Protein argonaute-2. Chain: a. Synonym: hago2,argonaute risc catalytic component 2,eukaryotic translation initiation factor 2c 2,eif2c 2,paz piwi domain protein, ppd,protein slicer. Engineered: yes. Mutation: yes. Sirna. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ago2, eif2c2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

2.50Å R-factor: 0.218 R-free: 0.248

Authors:

N.T.Schirle,I.J.Macrae

Key ref:

N.T.Schirle et al. (2016). Structural Analysis of Human Argonaute-2 Bound to a Modified siRNA Guide. J Am Chem Soc, 138, 8694-8697. PubMed id: 27380263 DOI: 10.1021/jacs.6b04454

Date:

07-May-16 Release date: 20-Jul-16

Protein chain

Q9UKV8  (AGO2_HUMAN) -  Protein argonaute-2 from Homo sapiens

Seq: 859 a.a.

Struc: 801 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DNA/RNA chain

U-U-A-U-C-U-A-U-A-A 10 bases

Enzyme reactions

• Enzyme class: E.C.3.1.26.n2 - ?????

DOI no: 10.1021/jacs.6b04454

J Am Chem Soc 138:8694-8697 (2016)

PubMed id: 27380263

Structural Analysis of Human Argonaute-2 Bound to a Modified siRNA Guide.

N.T.Schirle, G.A.Kinberger, H.F.Murray, W.F.Lima, T.P.Prakash, I.J.MacRae.

ABSTRACT

Incorporation of chemical modifications into small interfering RNAs (siRNAs) increases their metabolic stability and improves their tissue distribution. However, how these modifications impact interactions with Argonaute-2 (Ago2), the molecular target of siRNAs, is not known. Herein we present the crystal structure of human Ago2 bound to a metabolically stable siRNA containing extensive backbone modifications. Comparison to the structure of an equivalent unmodified-siRNA complex indicates that the structure of Ago2 is relatively unaffected by chemical modifications in the bound siRNA. In contrast, the modified siRNA appears to be much more plastic and shifts, relative to the unmodified siRNA, to optimize contacts with Ago2. Structure-activity analysis reveals that even major conformational perturbations in the 3' half of the siRNA seed region have a relatively modest effect on knockdown potency. These findings provide an explanation for a variety of modification patterns tolerated in siRNAs and a structural basis for advancing therapeutic siRNA design.