PDBsum entry 2o8c

DNA binding protein/DNA

PDB id

2o8c

Contents

			Protein chains

					830 a.a.


					932 a.a.

			DNA/RNA

			Ligands

					ADP ×2

			Metals

					_MG ×2

			Waters ×22

References listed in PDB file

Key reference

Title

Structure of the human mutsalpha DNA lesion recognition complex.

Authors

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

Ref.

Mol Cell, 2007, 26, 579-592. [DOI no: 10.1016/j.molcel.2007.04.018]

PubMed id

17531815

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.



	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.

PROCHECK

	Headers