Mitogen-activated protein kinase kinase
mitogen-activated protein (MAP) kinase kinase is a member of the protein kinase superfamily and is a Ser/Thr type kinase. It catalyses the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. It also acts on serine residues.
Reference Protein and Structure
- Sequence
-
P36507
(2.7.12.2)
(Sequence Homologues)
(PDB Homologues)
- Biological species
-
Homo sapiens (Human)
- PDB
-
1s9i
- X-ray structure of the human mitogen-activated protein kinase kinase 2 (MEK2)in a complex with ligand and MgATP
(3.2 Å)
- Catalytic CATH Domains
-
1.10.510.10
(see all for 1s9i)
- Cofactors
- Magnesium(2+) (1) Metal MACiE
Enzyme Reaction (EC:2.7.12.2)
+
→
+
+
Alternative enzyme names: MAP kinase kinase, MAP kinase kinase 4, MAP kinase kinase 7, MAP kinase or ERK kinase, MAP2K, MAPKK, MAPKK1, MEK, MEK1, MEK2, MKK, MKK2, MKK4, MKK6, MKK7, STK27,
Enzyme Mechanism
Introduction
The serine residue of the protein substrate attacks the terminal, pentavalent phosphorous of ATP. Asp194 abstracts a proton from the phospho-serine residue. Asp194 relays the proton to ADP, regenerating the active site.
Catalytic Residues Roles
| UniProt | PDB* (1s9i) | ||
| Asp194 | Asp194(140)A | Asp194 acts as a general base once the nucleophilic attack has taken place. | hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor |
| Asp221 | Asp221(167)A | Asp221 directs the phosphate chain into the correct alignment for nucleophilic attack by chelating to the associated Mg(II) cation | attractive charge-charge interaction, electrostatic stabiliser, steric role |
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file;
y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain;
C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.
Chemical Components
bimolecular nucleophilic substitution, overall reactant used, intermediate formation, proton transfer, overall product formed, proton relay, native state of enzyme regeneratedReferences
- Adams JA (2001), Chem Rev, 101, 2271-2290. Kinetic and Catalytic Mechanisms of Protein Kinases. DOI:10.1021/cr000230w. PMID:11749373.
- Anderson VE et al. (2006), Chem Rev, 106, 3236-3251. Activation of Oxygen Nucleophiles in Enzyme Catalysis. DOI:10.1021/cr050281z. PMID:16895326.
- Ohren JF et al. (2004), Nat Struct Mol Biol, 11, 1192-1197. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. DOI:10.1038/nsmb859. PMID:15543157.
- Gopalbhai K et al. (2003), J Biol Chem, 278, 8118-8125. Negative Regulation of MAPKK by Phosphorylation of a Conserved Serine Residue Equivalent to Ser212 of MEK1. DOI:10.1074/jbc.m211870200. PMID:12506122.
- Hanks SK et al. (1995), FASEB J, 9, 576-596. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. PMID:7768349.
- Zheng J et al. (1993), Acta Crystallogr D Biol Crystallogr, 49, 362-365. 2.2 Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. DOI:10.1107/s0907444993000423. PMID:15299527.
Step 1. The serine residue (which is not deprotonated prior to the attack) of the protein substrate attacks the terminal, pentavalent phosphorous of ATP. The transition state is mainly dissociative in character.
Download: Image, Marvin FileCatalytic Residues Roles
| Residue | Roles |
|---|---|
| Asp194(140)A | hydrogen bond acceptor |
| Asp221(167)A | attractive charge-charge interaction, electrostatic stabiliser, steric role |
Chemical Components
ingold: bimolecular nucleophilic substitution, overall reactant used, intermediate formation
Catalytic Residues Roles
| Residue | Roles |
|---|---|
| Asp194(140)A | hydrogen bond acceptor |
| Asp221(167)A | attractive charge-charge interaction, steric role, electrostatic stabiliser |
| Asp194(140)A | proton acceptor |
Chemical Components
proton transfer, overall product formed
Catalytic Residues Roles
| Residue | Roles |
|---|---|
| Asp194(140)A | hydrogen bond donor |
| Asp221(167)A | attractive charge-charge interaction, electrostatic stabiliser, steric role |
| Asp194(140)A | proton donor |
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