PDBsum entry 3ha8

Transferase

PDB id: 3ha8

Contents

Protein chain

342 a.a. *

Ligands

5JZ

Waters ×49

* Residue conservation analysis

PDB id:

3ha8

Name:

Transferase

Title:

The complex structure of the map kinase p38/compound 14b

Structure:

Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38 alpha, map kinase p38 alpha, cytokine suppressive anti-inflammatory drug-binding protein, csaid-binding protein, csbp, max-interacting protein 2, map kinase mxi2, sapk2a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csbp, csbp1, csbp2, cspb1, mapk14, mxi2, p38. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.48Å R-factor: 0.217 R-free: 0.248

Authors:

B.Zhao,M.A.Clark

Key ref:

M.A.Clark et al. (2009). Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat Chem Biol, 5, 647-654. PubMed id: 19648931 DOI: 10.1038/nchembio.211

Date:

01-May-09 Release date: 04-Aug-09

Protein chain

Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14 from Homo sapiens

Seq: 360 a.a.

Struc: 342 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.24 - mitogen-activated 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⁺

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

reference

DOI no: 10.1038/nchembio.211

Nat Chem Biol 5:647-654 (2009)

PubMed id: 19648931

Design, synthesis and selection of DNA-encoded small-molecule libraries.

M.A.Clark, R.A.Acharya, C.C.Arico-Muendel, S.L.Belyanskaya, D.R.Benjamin, N.R.Carlson, P.A.Centrella, C.H.Chiu, S.P.Creaser, J.W.Cuozzo, C.P.Davie, Y.Ding, G.J.Franklin, K.D.Franzen, M.L.Gefter, S.P.Hale, N.J.Hansen, D.I.Israel, J.Jiang, M.J.Kavarana, M.S.Kelley, C.S.Kollmann, F.Li, K.Lind, S.Mataruse, P.F.Medeiros, J.A.Messer, P.Myers, H.O'Keefe, M.C.Oliff, C.E.Rise, A.L.Satz, S.R.Skinner, J.L.Svendsen, L.Tang, K.van Vloten, R.W.Wagner, G.Yao, B.Zhao, B.A.Morgan.

ABSTRACT

Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.

Selected figure(s)

Figure 3.
(a) Selection output from DEL-A selections against Aurora A kinase. Low occurrence molecules (<4 copies) have been removed. Both selections show lines in the cycle 2 plane corresponding to 6-aminoquinoline. In method A, the line comprises 2-methoxyphenethylamine at cycle 3. In method B, there are two lines corresponding to 3,4-dimethoxyaniline and 4-pyrrolidinopiperidine at cycle 3. (b) Histograms showing the total occurrences of cycle 1 synthons after Aurora A selections. Using both methods, 7-AT is the highest occurring cycle 1 synthon. (c) Structures of synthesized compounds and their activity data. The compounds consist of members of both the 7-AT and the 6-aminoquinoline families. (d) Crystal structure of compound 10 bound to Aurora A kinase, showing the 2-fluorophenethylamine moiety exposed to solvent. Image created in Accelrys DS Viewer Pro 5.0.

The above figure is reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2009, 5, 647-654) copyright 2009.

Figure was selected by an automated process.