PDBsum entry 1u54

Transferase

PDB id: 1u54

Contents

Protein chains

263 a.a. *

Ligands

ACP ×2

Metals

_MG ×4

Waters ×10

* Residue conservation analysis

PDB id:

1u54

Name:

Transferase

Title:

Crystal structures of the phosphorylated and unphosphorylated kinase domains of the cdc42-associated tyrosine kinase ack1 bound to amp-pcp

Structure:

Activated cdc42 kinase 1. Chain: a. Fragment: kinase domain. Synonym: ack-1. Engineered: yes. Other_details: phosphorylated at residue 284. Activated cdc42 kinase 1. Chain: b. Fragment: kinase domain.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ack1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf-9.

Resolution:

2.80Å R-factor: 0.226 R-free: 0.322

Authors:

J.C.Lougheed,R.H.Chen,P.Mak,T.J.Stout

Key ref:

J.C.Lougheed et al. (2004). Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1. J Biol Chem, 279, 44039-44045. PubMed id: 15308621 DOI: 10.1074/jbc.M406703200

Date:

26-Jul-04 Release date: 31-Aug-04

Protein chains

Q07912  (ACK1_HUMAN) -  Activated CDC42 kinase 1 from Homo sapiens

Seq: 1038 a.a.

Struc: 263 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.7.10.2 - non-specific 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(+)

• Enzyme class 3: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

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

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

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

DOI no: 10.1074/jbc.M406703200

J Biol Chem 279:44039-44045 (2004)

PubMed id: 15308621

Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1.

J.C.Lougheed, R.H.Chen, P.Mak, T.J.Stout.

ABSTRACT

ACK1 is a multidomain non-receptor tyrosine kinase that is an effector of the Cdc42 GTPase. Members of the ACK family have a unique domain ordering and are the only tyrosine kinases known to interact with Cdc42. In contrast with many protein kinases, ACK1 has only a modest increase in activity upon phosphorylation. We have solved the crystal structures of the human ACK1 kinase domain in both the unphosphorylated and phosphorylated states. Comparison of these structures reveals that ACK1 adopts an activated conformation independent of phosphorylation. Furthermore, the unphosphorylated activation loop is structured, and its conformation resembles that seen in activated tyrosine kinases. In addition to the apo structure, complexes are also presented with a non-hydrolyzable nucleotide analog (adenosine 5'-(beta,gamma-methylenetriphosphate)) and with the natural product debromohymenialdisine, a general inhibitor of many protein kinases. Analysis of these structures reveals a typical kinase fold, a pre-organization into the activated conformation, and an unusual substrate-binding cleft.

Selected figure(s)

Figure 2.
FIG. 2. Structure of ACK1K bound to a nucleotide analog (AMP-PCP). An F[o] - F[c] omit map of AMP-PCP and the two bound magnesium ions is contoured at 2.5 . For simplicity, only the unphosphorylated molecule bound to AMP-PCP is shown. Hydrogen bonds are shown as dashed lines. Magnesium ions are shown in yellow, and the magnesium-binding residues Asn257 and Asp270 are labeled. The side chain of Ser212 is pointing away from the ribose rather than forming a hydrogen bond with the ribose 2'-hydroxyl. The conserved salt bridge (Lys158-Glu177) is also shown.

Figure 3.
FIG. 3. Comparison of activation loops in several structures. Residues 271-290 of the ACK1K activation loop (a-c) and the corresponding residues in IRK3P (d) are shown. a and b, comparison of the unphosphorylated activation loop of the apo-ACK1K structure and the phosphorylated activation loop of the AMP-PCP complex, respectively. The unphosphorylated loop is structured and adopts a global conformation similar to that of the phosphorylated loop. Residues that shift in position upon phosphorylation are shown in both loops. Residues that could not be well placed in electron density are orange. Arg251 (catalytic loop) forms a hydrogen bond with Tyr(P)284 and is also included. c and d, comparison of the unphosphorylated activation loop of ACK1K and the phosphorylated activation loop of IRK3P, respectively. The unphosphorylated ACK1K activation loop (c) is stabilized by several interactions that differ from those found in other kinase activation loops. The residues involved in these interactions and the corresponding residues in IRK3P (d) are shown.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 44039-44045) copyright 2004.

Figures were selected by the author.