PDBsum entry: 2o8e

DNA binding protein/DNA

PDB-id: 2o8e

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Description

Header details

Header records

References

PROCHECK

Protein chains

824 a.a. *

935 a.a. *

DNA/RNA

Ligands

ADP

Metal ions

_MG

Waters ×10

* Residue conservation analysis

Tools

Clefts Calculation

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PDB id:

2o8e

Name:

DNA binding protein/DNA

Title:

Human mutsalpha (msh2/msh6) bound to a g t mispair, with adp bound to msh2 only

Structure:

5'- d( Gp Ap Ap Cp Cp Gp Cp Gp Gp Gp Cp Tp Ap Gp G)-3'. Chain: e. Engineered: yes. Mutation: yes. 5'- d( Cp Cp Tp Ap Gp Cp Cp Tp Gp Cp Gp Gp Tp Tp C)-3'. Chain: f. Engineered: yes.

Source:

Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Gene: msh2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: msh6, gtbp.

UniProt:

Chain A: P43246 (MSH2_HUMAN)

Seq:
Struc:
	Seq:
	Struc:
Seq:
Struc:
	Seq:	934 a.a.
	Struc:	824 a.a.*

Chain B: P52701 (MSH6_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

Struc:

Seq:

Struc:

Seq:

Struc:

Seq:

1360 a.a.

Struc:

935 a.a.

Key:	PfamA domain	PfamB domain
Secondary structure

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

Resolution:

3.30Å

R-factor:

0.255

R-free:

0.291

Authors:

J.J.Warren,T.J.Pohlhaus,A.Changela,P.L.Modrich,L.S.Beese

Key ref:

J.J.Warren et al. (2007). Structure of the Human MutSalpha DNA Lesion Recognition Complex.. Mol Cell, 26, 579-592. [PubMed id: 17531815] [DOI: 10.1016/j.molcel.2007.04.018]

Date:

12-Dec-06

Release date:

05-Jun-07

Related entries:

2o8b
human mutsalpha (msh2/msh6) bound to adp and a g t mispair
2o8c
human mutsalpha (msh2/msh6) bound to adp and a g du mispair
2o8d
human mutsalpha (msh2/msh6) bound to adp and a g du mispair
2o8f
human mutsalpha (msh2/msh6) bound to DNA with a single base
t insert

Quick_links

Procheck

Surface

Key reference

DOI no: 10.1016/j.molcel.2007.04.018

Mol Cell 26:579-592 (2007)

PubMed id: 17531815

Structure of the Human MutSalpha DNA Lesion Recognition Complex.

J.J.Warren, T.J.Pohlhaus, A.Changela, R.R.Iyer, P.L.Modrich, L.S.Beese.

ABSTRACT

Mismatch repair (MMR) ensures the fidelity of DNA replication, initiates the cellular response to certain classes of DNA damage, and has been implicated in the generation of immune diversity. Each of these functions depends on MutSalpha (MSH2*MSH6 heterodimer). Inactivation of this protein complex is responsible for tumor development in about half of known hereditary nonpolyposis colorectal cancer kindreds and also occurs in sporadic tumors in a variety of tissues. Here, we describe a series of crystal structures of human MutSalpha bound to different DNA substrates, each known to elicit one of the diverse biological responses of the MMR pathway. All lesions are recognized in a similar manner, indicating that diversity of MutSalpha-dependent responses to DNA lesions is generated in events downstream of this lesion recognition step. This study also allows rigorous mapping of cancer-causing mutations and furthermore suggests structural pathways for allosteric communication between different regions within the heterodimer.

Selected figure(s)

Figure 1.
Figure 1. Overview of the Structure of Human MutSα
(A) Ribbon diagram of the structure of a MutSα/ADP/G•T mispair complex. Blue, MSH6; red, MSH2; green ribbon, DNA; yellow, ADP; and green spheres, Mg^2+ ions. Positions of the ABC ATPase domains and the two channels in MutSα are indicated. Long α helices connecting clamp and ATPase domains in MSH2 and MSH6 are colored orange and cyan, respectively.
(B) Orthogonal, expanded view of the DNA binding domains of MutSα. DNA is shown as sticks, colored by atom type, with the central G•T mispair colored yellow.
(C) Expanded view of the upper channel in MutSα, colored as in (A) and shown as ribbons and a transparent surface. Disordered loops are shown as dashed lines with residue numbers.
(D) The domain structure of MSH6. Center: domains 1–5 are colored blue, green, yellow, orange, and red, respectively. Periphery: exploded view of each domain, labeled and colored with blue-red “chainbows” from the N- to C termini of the domain. Figures were generated with PyMOL (DeLano, 2002).

Figure 5.
Figure 5. Common Binding Mode for MutSα Substrates
(A) Interactions between a G•T mispair and an adjacent base pair with MSH6 domain 1 (shown as sticks under a semitransparent electrostatic surface).
(B) Protein-mispair contacts in a MutSα/G•dU/DNA complex. Putative hydrogen bonds are shown as dashed lines. Interacting residues (defined with LIGPLOT [Wallace et al., 1995]) are labeled. Orientation is rotated vert, similar 90° from (A).
(C) Protein mispair contacts in a MutSα/O^6-methyl-guanine/DNA complex, colored, labeled, and oriented as in (B).
(D) Interactions between a single base T insert substrate (cyan carbons) or a G•T mispair (green carbons) substrate and MSH6 domain 1 (blue surface). Hydrogen bonds are shown as dashed lines. Orientation is approximately the same as (A).
(E) Protein-DNA interactions in the MutSα-DNA complex. Amino acids that make hydrogen bonding (red lines) or van der Waals interactions (gray lines) are indicated with blue text (MSH6) or red text (MSH2). Dashed lines group the amino acids by protein domain as indicated. Interactions were classified by using Probe (Word et al., 1999).
(F) Structures with G•T (red), T insert (green) were superimposed on domain 1 of MSH6. DNAs from both complexes are shown as sticks, and backbone traces of MSH2 are shown as ribbons and surfaces. The arrow indicates the movement of domains 4 and 3 of MSH2 in the insert structure that compensates for the slight change in the DNA substrate register.

The above figures are reprinted by permission from Cell Press: Mol Cell (2007, 26, 579-592) copyright 2007.

Figures were selected by the author.