PDBsum entry 1k3a

Transferase

PDB id: 1k3a

Contents

Protein chain

291 a.a. *

Ligands

GLY-GLU-TYR-VAL-ASN-ILE-GLU-PHE

ACP

Waters ×158

* Residue conservation analysis

PDB id:

1k3a

Name:

Transferase

Title:

Structure of the insulin-like growth factor 1 receptor kinase

Structure:

Insulin-like growth factor 1 receptor. Chain: a. Fragment: beta chain, kinase domain (residues 988-1286). Engineered: yes. Insulin receptor substrate 1. Chain: b. Synonym: irs-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Other_details: chemically synthesized

Biol. unit:

Dimer (from PQS)

Resolution:

2.10Å R-factor: 0.212 R-free: 0.251

Authors:

S.Favelyukis,J.H.Till,S.R.Hubbard,W.T.Miller

Key ref:

S.Favelyukis et al. (2001). Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol, 8, 1058-1063. PubMed id: 11694888 DOI: 10.1038/nsb721

Date:

02-Oct-01 Release date: 28-Nov-01

Protein chain

P08069  (IGF1R_HUMAN) -  Insulin-like growth factor 1 receptor from Homo sapiens

Seq: 1367 a.a.

Struc: 291 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = ACP) matches with 81.25% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/nsb721

Nat Struct Biol 8:1058-1063 (2001)

PubMed id: 11694888

Structure and autoregulation of the insulin-like growth factor 1 receptor kinase.

S.Favelyukis, J.H.Till, S.R.Hubbard, W.T.Miller.

ABSTRACT

The insulin-like growth factor 1 (IGF1) receptor is closely related to the insulin receptor. However, the unique biological functions of IGF1 receptor make it a target for therapeutic intervention in human cancer. Using its isolated tyrosine kinase domain, we show that the IGF1 receptor is regulated by intermolecular autophosphorylation at three sites within the kinase activation loop. Steady-state kinetic analyses of the isolated phosphorylated forms of the IGF1 receptor kinase (IGF1RK) reveal that each autophosphorylation event increases enzyme turnover number and decreases Km for ATP and peptide. We have determined the 2.1 A-resolution crystal structure of the tris-phosphorylated form of IGF1RK in complex with an ATP analog and a specific peptide substrate. The structure of IGF1RK reveals how the enzyme recognizes peptides containing hydrophobic residues at the P+1 and P+3 positions and how autophosphorylation stabilizes the activation loop in a conformation that facilitates catalysis. Although the nucleotide binding cleft is conserved between IGF1RK and the insulin receptor kinase, sequence differences in the nearby interlobe linker could potentially be exploited for anticancer drug design.

Selected figure(s)

Figure 2.
Figure 2. Overall structure of IGF1RK and activation loop interactions. a, Ribbon diagram of the IGF1RK structure. -strands (numbered) are shown in cyan; -helices (lettered), in red. The peptide is colored orange with the phosphate-acceptor Tyr shown in ball-and-stick representation. The nucleotide analog, AMP-PCP, is also shown in ball-and-stick representation (black). The dashed gray coil represents the disordered portion of the kinase insert. The N-terminal (NT) end of the structure is labeled. The C-terminal end is after J, hidden behind 8. b, Interactions within the A-loop (in stereo). The A-loop (residues 1,123 -1,145) is shown as a backbone worm (green) with side chains of selected residues shown in stick representation (carbon = green, nitrogen = blue, oxygen = red, sulfur = yellow and phosphorus = black). Residues contributing to stabilization of the activation loop via hydrophobic interactions are shown with a molecular surface. Hydrogen bonds are shown as dashed lines (black). c, Interactions between the A-loop and other kinase segments (in stereo). A backbone worm representation is shown for the A-loop (green), a segment including part of the catalytic loop (residues 1,100 -1,105 in orange) and a segment corresponding to 12 (residues 1,157 -1,159 in gray). Side chain and main chain atoms are shown in stick representation with the same color scheme as in (b) with the exception of carbon, which is colored the same as the corresponding backbone worm. For clarity, pTyr 1136 has been omitted.

Figure 3.
Figure 3. IGF1RK peptide substrate binding and comparison to IRK. a, Stereo view of the 2F[o] - F[c] electron density map (2.1 Å resolution, 1 contour) for the peptide substrate. The electron density is shown as a wire mesh (blue); the peptide substrate (orange), in stick representation. b, Stereo view of interactions at the IGF1RK -peptide substrate interface. A semitransparent molecular surface (gray) of IGF1RK is shown with residues (labeled and displayed in stick representation) that define the peptide binding cleft and interact with the peptide substrate. The peptide (shown in stick representation) is illustrated without a molecular surface, with residues labeled relative to the phosphate acceptor Tyr (P0). Hydrogen bonds between the peptide and the enzyme are shown as black lines. Bond coloring is carbon = orange, oxygen = red, nitrogen = blue, sulfur = green and phosphorus = yellow. c, A molecular surface representation of IGF1RK illustrating surface residue differences between IGF1RK and IRK. The molecular surface contributed by differing side chains between the two structures are colored green. The molecular surface contributed by the Thr 1053 side chain in the interlobe linker is colored yellow (see text). d, A backbone worm representation of IGF1RK. Segments corresponding to residues that differ between IGF1RK and IRK are colored green. In (c,d), stick representations of the nucleotide analog (AMP-PCP) and peptide are shown. The semitransparent segment represents the portion of the kinase insert disordered in the structure. Bond coloring is the same as in (a).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2001, 8, 1058-1063) copyright 2001.

Figures were selected by an automated process.