PDBsum entry 1b55

Transferase

PDB id: 1b55

Contents

Protein chains

163 a.a. *

Ligands

4IP ×2

Metals

_ZN ×2

Waters ×196

* Residue conservation analysis

PDB id:

1b55

Name:

Transferase

Title:

Ph domain from bruton's tyrosine kinase in complex with inositol 1,3, 4,5-tetrakisphosphate

Structure:

Tyrosine-protein kinase btk. Chain: a, b. Fragment: ph domain and btk motif. Synonym: bruton's agammaglobulinemia tyrosine kinase, btk. Engineered: yes. Other_details: complex with inositol 1,3,4,5-tetrakisphosphate

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Cell: b-lymphocyte. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.40Å R-factor: 0.234 R-free: 0.350

Authors:

K.Djinovic Carugo,E.Baraldi,M.Hyvoenen,P.Lo Surdo,A.M.Riley, B.V.L.Potter,R.O'Brien,J.E.Ladbury,M.Saraste

Key ref:

E.Baraldi et al. (1999). Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate. Structure, 7, 449-460. PubMed id: 10196129 DOI: 10.1016/S0969-2126(99)80057-4

Date:

12-Jan-99 Release date: 15-Jun-99

Protein chains

Q06187  (BTK_HUMAN) -  Tyrosine-protein kinase BTK from Homo sapiens

Seq: 659 a.a.

Struc: 163 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

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

Added reference

DOI no: 10.1016/S0969-2126(99)80057-4

Structure 7:449-460 (1999)

PubMed id: 10196129

Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate.

E.Baraldi, K.D.Carugo, M.Hyvönen, P.L.Surdo, A.M.Riley, B.V.Potter, R.O'Brien, J.E.Ladbury, M.Saraste.

ABSTRACT

BACKGROUND: The activity of Bruton's tyrosine kinase (Btk) is important for the maturation of B cells. A variety of point mutations in this enzyme result in a severe human immunodeficiency known as X-linked agammaglobulinemia (XLA). Btk contains a pleckstrin-homology (PH) domain that specifically binds phosphatidylinositol 3,4,5-trisphosphate and, hence, responds to signalling via phosphatidylinositol 3-kinase. Point mutations in the PH domain might abolish membrane binding, preventing signalling via Btk. RESULTS: We have determined the crystal structures of the wild-type PH domain and a gain-of-function mutant E41K in complex with D-myo-inositol 1,3,4,5-tetra-kisphosphate (Ins (1,3,4,5)P4). The inositol Ins (1,3,4,5)P4 binds to a site that is similar to the inositol 1,4,5-trisphosphate binding site in the PH domain of phospholipase C-delta. A second Ins (1,3,4,5)P4 molecule is associated with the domain of the E41K mutant, suggesting a mechanism for its constitutive interaction with membrane. The affinities of Ins (1,3,4,5)P4 to the wild type (Kd = 40 nM), and several XLA-causing mutants have been measured using isothermal titration calorimetry. CONCLUSIONS: Our data provide an explanation for the specificity and high affinity of the interaction with phosphatidylinositol 3,4,5-trisphosphate and lead to a classification of the XLA mutations that reside in the Btk PH domain. Mis-sense mutations that do not simply destabilize the PH fold either directly affect the interaction with the phosphates of the lipid head group or change electrostatic properties of the lipid-binding site. One point mutation (Q127H) cannot be explained by these facts, suggesting that the PH domain of Btk carries an additional function such as interaction with a Galpha protein.

Selected figure(s)

Figure 4.
Figure 4. Comparison between the inositol phoshate binding sites in the (a) Btk PH domain and (b) in the PLC-d PH domain [31]. Only the residues that are most important for the interaction are indicated and coloured red and orange. K12 and R28 in Btk superimpose with K30 and R40 in PLC-d. The Ins(1,3,4,5)P[4] in Btk and the Ins(1,4,5)P[3]in PLC-d are in cyan.

The above figure is reprinted by permission from Cell Press: Structure (1999, 7, 449-460) copyright 1999.

Figure was selected by an automated process.