KLIFS: a knowledge-based structural database to navigate kinase-ligand interaction space

O.P.J. van Linden, A.J. Kooistra, R. Leurs, I.J.P. de Esch, C. de Graaf

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies.

Original languageEnglish
Pages (from-to)249-277
Number of pages29
JournalJournal of Medicinal Chemistry
Volume57
Issue number2
DOIs
Publication statusPublished - 2013

Fingerprint

Dermatoglyphics
Phosphotransferases
Databases
Ligands
Designer Drugs
Protein Kinases
Signal Transduction
Catalytic Domain
Binding Sites

Keywords

  • Binding Sites
  • Data Mining
  • Databases, Protein
  • Drug Discovery
  • Humans
  • Hydrogen Bonding
  • Knowledge Bases
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors
  • Protein Kinases
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

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title = "KLIFS: a knowledge-based structural database to navigate kinase-ligand interaction space",
abstract = "Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies.",
keywords = "Binding Sites, Data Mining, Databases, Protein, Drug Discovery, Humans, Hydrogen Bonding, Knowledge Bases, Ligands, Models, Molecular, Protein Binding, Protein Conformation, Protein Kinase Inhibitors, Protein Kinases, Journal Article, Research Support, Non-U.S. Gov't",
author = "{van Linden}, O.P.J. and A.J. Kooistra and R. Leurs and {de Esch}, I.J.P. and {de Graaf}, C.",
year = "2013",
doi = "10.1021/jm400378w",
language = "English",
volume = "57",
pages = "249--277",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
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KLIFS : a knowledge-based structural database to navigate kinase-ligand interaction space. / van Linden, O.P.J.; Kooistra, A.J.; Leurs, R.; de Esch, I.J.P.; de Graaf, C.

In: Journal of Medicinal Chemistry, Vol. 57, No. 2, 2013, p. 249-277.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - KLIFS

T2 - a knowledge-based structural database to navigate kinase-ligand interaction space

AU - van Linden, O.P.J.

AU - Kooistra, A.J.

AU - Leurs, R.

AU - de Esch, I.J.P.

AU - de Graaf, C.

PY - 2013

Y1 - 2013

N2 - Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies.

AB - Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies.

KW - Binding Sites

KW - Data Mining

KW - Databases, Protein

KW - Drug Discovery

KW - Humans

KW - Hydrogen Bonding

KW - Knowledge Bases

KW - Ligands

KW - Models, Molecular

KW - Protein Binding

KW - Protein Conformation

KW - Protein Kinase Inhibitors

KW - Protein Kinases

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1021/jm400378w

DO - 10.1021/jm400378w

M3 - Article

VL - 57

SP - 249

EP - 277

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -