PDBsum entry 4d2v

Transferase

PDB id: 4d2v

Contents

Protein chains

313 a.a.

318 a.a.

Ligands

45R ×4

Waters ×544

PDB id:

4d2v

Name:

Transferase

Title:

Structure of melk in complex with inhibitors

Structure:

Maternal embryonic leucine zipper kinase. Chain: a, b, c, d. Synonym: hmelk, protein kinase eg3, peg3 kinase, protein kinase pk38, hpk38, tyrosine-protein kinase melk, hmelk, protein kinase eg3, peg3 kinase, protein kinase pk38, hpk38, tyrosine-protein kinase melk, melk. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Other_details: image clone

Resolution:

2.45Å R-factor: 0.295 R-free: 0.357

Authors:

C.N.Johnson,V.Berdini,L.Beke,P.Bonnet,D.Brehmer,J.E.Coyle,P.J.Day, M.Frederickson,E.J.E.Freyne,R.A.H.J.Gilissen,C.C.F.Hamlett,S.Howard, L.Meerpoel,R.Mcmenamin,S.Patel,D.C.Rees,A.Sharff,F.Sommen,T.Wu, J.T.M.Linders

Key ref:

C.N.Johnson et al. (2015). Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase. Acs Med Chem Lett, 6, 25-30. PubMed id: 25589925 DOI: 10.1021/ml5001245

Date:

13-May-14 Release date: 15-Oct-14

Protein chains

Q14680  (MELK_HUMAN) -  Maternal embryonic leucine zipper kinase from Homo sapiens

Seq: 651 a.a.

Struc: 313 a.a.*

Protein chain

Q14680  (MELK_HUMAN) -  Maternal embryonic leucine zipper kinase from Homo sapiens

Seq: 651 a.a.

Struc: 318 a.a.*

* PDB and UniProt seqs differ at 12 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chains A, B, C, D: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺
• Enzyme class 3: Chains A, B, C, D: 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⁺

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: 10.1021/ml5001245

Acs Med Chem Lett 6:25-30 (2015)

PubMed id: 25589925

Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase.

C.N.Johnson, V.Berdini, L.Beke, P.Bonnet, D.Brehmer, J.E.Coyle, P.J.Day, M.Frederickson, E.J.Freyne, R.A.Gilissen, C.C.Hamlett, S.Howard, L.Meerpoel, R.McMenamin, S.Patel, D.C.Rees, A.Sharff, F.Sommen, T.Wu, J.T.Linders.

ABSTRACT

Fragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 μM) fragment hit was identified, which bound to the hinge region with an atypical binding mode, and this was optimized using structure-based design into a low-nanomolar and cell-penetrant inhibitor, with a good selectivity profile, suitable for use as a chemical probe for elucidation of MELK biology.