PDBsum entry: 1d4v

Apoptosis

PDB id: 1d4v

Contents

Protein chains

163 a.a. *

117 a.a. *

Waters ×154

* Residue conservation analysis

PDB id:

1d4v

Name:

Apoptosis

Title:

Crystal structure of trail-dr5 complex

Structure:

Tnf-related apoptosis inducing ligand. Chain: b. Fragment: single subunit. Synonym: trail. Engineered: yes. Death receptor 5. Chain: a. Fragment: extracellular region. Synonym: dr5.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: transient expression as ig fusion protein. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell: 293t cells

Biol. unit:

Hexamer (from PDB file)

Resolution:

2.20Å R-factor: 0.221 R-free: 0.270

Authors:

J.Mongkolsapaya,J.M.Grimes,D.I.Stuart,E.Y.Jones,G.R.Screaton

Key ref:

J.Mongkolsapaya et al. (1999). Structure of the TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation. Nat Struct Biol, 6, 1048-1053. PubMed id: 10542098 DOI: 10.1038/14935

Date:

06-Oct-99 Release date: 01-Nov-99

Protein chain

P50591  (TNF10_HUMAN) -  Tumor necrosis factor ligand superfamily member 10

Seq: 281 a.a.

Struc: 163 a.a.

Protein chain

O14763  (TR10B_HUMAN) -  Tumor necrosis factor receptor superfamily member 10B

Seq: 440 a.a.

Struc: 117 a.a.*

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

 Gene Ontology (GO) functional annotation 

• Cellular component: membrane (1 term)
• Biological process: immune response (1 term)
• Biochemical function: receptor activity (2 terms)

DOI no: 10.1038/14935

Nat Struct Biol 6:1048-1053 (1999)

PubMed id: 10542098

Structure of the TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation.

J.Mongkolsapaya, J.M.Grimes, N.Chen, X.N.Xu, D.I.Stuart, E.Y.Jones, G.R.Screaton.

ABSTRACT

TRAIL, an apoptosis inducing ligand, has at least four cell surface receptors including the death receptor DR5. Here we report the crystal structure at 2.2 A resolution of a complex between TRAIL and the extracellular region of DR5. TRAIL forms a central homotrimer around which three DR5 molecules bind. Radical differences in the surface charge of the ligand, together with variation in the alignment of the two receptor domains confer specificity between members of these ligand and receptor families. The existence of a switch mechanism allowing variation in receptor domain alignment may mean that it is possible to engineer receptors with multiple specificities by exploiting contact positions unique to individual receptor-ligand pairs.

Selected figure(s)

Figure 1.
Figure 1. The structure of TRAIL, DR5 and the TRAIL−DR5 complex. a, Stereo view of the complex. The three crystallographically equivalent copies of the TRAIL subunit (yellow, cyan, pink) and DR5 (blue, green, red) are depicted schematically and the TRAIL trimer is enclosed in a transparent molecular envelope. This orientation defines a standard view. b, The complex as depicted in (a) but viewed down the three-fold axis. The orientation is such that the cell surface presenting DR5 is above the page and that for TRAIL is below the page. c, Superposition of TRAIL (pink) with TNF (blue). The secondary structure elements for TRAIL are also marked on the sequence alignment in Fig. 2a. The r.m.s. deviation is 0.9 Å for 120 structurally equivalent C atoms. The major extension of the AA" loop in TRAIL is highlighted by yellow stripes. The cell surface position is not to scale. d, Comparison of DR5 and TNF-R1. DR5 and TNF-R1 (from the TNF −TNF-R1 complex) are depicted schematically in the left and right panels respectively with equivalent regions in identical colors. The central panel is based on superposition of DR5 D1 and TNF-R1 D2. The schematic representation of TNF-R1 is shown in gray while that of DR5 is in green. Disulfide bonds are depicted in yellow as ball-and-stick representation. e, Portion of the final 2F[o] - F[c] electron density map contoured at 1 , showing a portion of the TRAIL structure in the BC loop.

Figure 3.
Figure 3. Elements of conservation and specificity in ligand−receptor binding. a, Conservation in ligand-receptor interactions. Close up of the interaction involving the B1 (cyan) surfaces in the TRAIL−DR5 and TNF −TNF-R1 complexes centered on the key tyrosine residue (Tyr 216 in TRAIL). In this and in (c), the polypeptide chains are represented schematically as in Fig. 1a and the solvent-accessible surfaces of the receptors (calculated in isolation) are shown as semi-transparent envelopes. b, Comparison of surface charge between TRAIL, TNF , TNF and their receptors. Blue denotes positive, and red negative; electrostatic potential is contoured at 8.0 kT in program GRASP^31. The views of ligand and receptor are as in Fig. 2b. c, Interaction of Arg 149 in the AA" loop of TRAIL with Glu 147 in DR5. d, BIAcore analysis showing binding of DR5 to wild type TRAIL or the mutant lacking the AA" loop. e, Immunoprecipitation with DR5-Fc in the presence of wild type (W) or the slightly smaller AA" TRAIL mutant (M). Lanes 1 and 2 immunoprecipitated material (IP), lanes 3 and 4 material left in supernatant (SN) following immunoprecipitation.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (1999, 6, 1048-1053) copyright 1999.

Figures were selected by the author.