PDBsum entry 2ec8

Transferase

PDB id: 2ec8

Contents

Protein chain

464 a.a. *

Ligands

NAG ×5

* Residue conservation analysis

PDB id:

2ec8

Name:

Transferase

Title:

Crystal structure of the exctracellular domain of the receptor tyrosine kinase, kit

Structure:

Mast/stem cell growth factor receptor. Chain: a. Fragment: extracellular domains, d1-d5. Synonym: scfr, proto-oncogene tyrosine-protein kinase kit, c-kit, cd117 antigen. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kit. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

3.00Å R-factor: 0.256 R-free: 0.295

Authors:

S.Yuzawa,Y.Opatowsky,Z.Zhang,V.Mandiyan,I.Lax,J.Schlessinger

Key ref:

S.Yuzawa et al. (2007). Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell, 130, 323-334. PubMed id: 17662946 DOI: 10.1016/j.cell.2007.05.055

Date:

11-Feb-07 Release date: 07-Aug-07

Protein chain

P10721  (KIT_HUMAN) -  Mast/stem cell growth factor receptor Kit from Homo sapiens

Seq: 976 a.a.

Struc: 464 a.a.

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 = NAG) matches with 41.38% similarity) + ADP + H(+)

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

Added reference

DOI no: 10.1016/j.cell.2007.05.055

Cell 130:323-334 (2007)

PubMed id: 17662946

Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor.

S.Yuzawa, Y.Opatowsky, Z.Zhang, V.Mandiyan, I.Lax, J.Schlessinger.

ABSTRACT

Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the ectodomain of KIT, resulting in tyrosine kinase activation. We describe the crystal structure of the entire ectodomain of KIT before and after SCF stimulation. The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. Receptor dimerization is followed by conformational changes that enable lateral interactions between membrane proximal Ig-like domains D4 and D5 of two KIT molecules. Experiments with cultured cells show that KIT activation is compromised by point mutations in amino acids critical for D4-D4 interaction. Moreover, a variety of oncogenic mutations are mapped to the D5-D5 interface. Since key hallmarks of KIT structures, ligand-induced receptor dimerization, and the critical residues in the D4-D4 interface, are conserved in other receptors, the mechanism of KIT stimulation unveiled in this report may apply for other receptor activation.

Selected figure(s)

Figure 2.
Figure 2. Crystal Structure of the SCF-KIT Ectodomain 2:2 Complex
(A) Ribbon diagram of the SCF-KIT 2:2 complex. Color coding of D1 to D5 is the same as in Figure 1 and SCF is colored in magenta. N and C termini of KIT and SCF are labeled. Disulfide bonds in D1 and D5 are shown in ball-and-stick rendering with sulfur atoms colored in orange. Asparagine-linked carbohydrates are represented in a stick model. Arrow marks a large cavity in the SCF-KIT 2:2 complex. (See stereo view in Figure S2.)
(B) Surface representations of the SCF-KIT ectodomain 2:2 complex. The figures show a top view (top), face view (center left), side view (center right), and bottom view (low). Color coding is the same as in (A). The views show that a SCF dimer interacts symmetrically with D1, D2, and D3 of two corresponding KIT ectodomains. In addition, KIT ectodomains form homophylic interactions through lateral contacts between D4 (orange) and between D5 (pink) of two neighboring receptors.

Figure 6.
Figure 6. Views of the D4-D4 and D5-D5 Interfaces
(A) 2Fo-Fc electron density map contoured at 1.1σ level showing a view of the D4-D4 interface (top panel). The backbones of KIT protomers are represented as pink and yellow tubes, respectively. A close view (bottom panel) of the D4-D4 interface of two neighboring ectodomains is shown. Interchain hydrogren bonds formed between Arg381 and Glu386 of two adjacent D4 are colored in yellow. Key amino acids are labeled and shown as a stick model. Secondary structure elements are labeled according to the IgSF nomenclature.
(B) Conservation of the D4-D4 dimerization motif across members of type III and type V RTK families. Residues 370–398 of human KIT (AAC50969.1) aligned with sequences of (with accession numbers) mouse (AAH75716.1), chicken (NP_989692.1), Xenopus laevis (AAH61947), salamander (AAS91161.1), and zebrafish (type A and B (NP_571128, XP_691901) homologs. Also shown are amino-acid sequences of CSF1R from human (P07333), mouse (P09581), and torafugu type A and B (P79750, Q8UVR8) and sequences from PDGFRα and PDGFRβ from human (P16234, P09619) and mouse (NP_035188, P05622). Amino-acid sequences of type V RTKs of human VEGFR type 1–3 (7^th Ig-like domain) (P17948, P35968, and P35916) are also presented. Secondary structure elements on KIT are labeled on the top of the sequence alignment. The conserved residues of Arg381 and Lys383, Leu382 and Leu379, and Glu386 and Gly388 are colored in blue, yellow, red, and green, respectively.
(C) Ribbon diagram of a D5-D5 interface. Strands A and G of two adjacent KIT protomers participate in formation of the D5-D5 interface. The D5-D5 interface is maintained by lateral interactions between Tyr418 and Asn505 of two neighboring receptors probably through ion(s) or water molecule(s).
(D) Electrostatic potential surfaces of D4 and D5 of KIT. The figures show a face view of the D4-D4 interacting surface (right) and a view following 90° rotation along the vertical axis (left). The position of acidic patch and the D4-D4 interfaces are circled and the interacting residue Arg381 and Glu386 are labeled.

The above figures are reprinted by permission from Cell Press: Cell (2007, 130, 323-334) copyright 2007.

Figures were selected by an automated process.