Structural basis of inhibitor selectivity in MAP kinases

Zhulun Wang, Bertram J. Canagarajah, Jeffrey C. Boehm, Skouki Kassisà, Melanie H. Cobb, Peter R. Young, Sherin Abdel-Meguid, Jerry L. Adams, Elizabeth J. Goldsmith

Research output: Contribution to journalArticle

395 Citations (Scopus)

Abstract

Background: The mitogen-activated protein (MAP) kinases are important signaling molecules that participate in diverse cellular events and are potential targets for intervention in inflammation, cancer, and other diseases. The MAP kinase p38 is responsive to environmental stresses and is involved in the production of cytokines during inflammation. In contrast, the activation of the MAP kinase ERK2 (extracellular-signal-regulated kinase 2) leads to cellular differentiation or proliferation. The anti-inflammatory agent pyridinylimidazole and its analogs (SB [SmithKline Beecham] compounds) are highly potent and selective inhibitors of p38, but not of the closely related ERK2, or other serine/threonine kinases. Although these compounds are known to bind to the ATP-binding site, the origin of the inhibitory specificity toward p38 is not clear. Results: We report the structural basis for the exceptional selectivity of these SB compounds for p38 over ERK2, as determined by comparative crystallography. In addition, structural data on the origin of olomoucine (a better inhibitor of ERK2) selectivity are presented. The crystal structures of four SB compounds in complex with p38 and of one SB compound and olomoucine in complex with ERK2 are presented here. The SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low-activity form of p38. The relatively closed domain structure of ERK2 is able to accommodate the smaller olomoucine. Conclusions: The unique kinase-inhibitor interactions observed in these complexes originate from amino-acid replacements in the active site and replacements distant from the active site that affect the size of the domain interface. This structural information should facilitate the design of better MAP-kinase inhibitors for the treatment of inflammation and other diseases.

Original languageEnglish (US)
Pages (from-to)1117-1128
Number of pages12
JournalStructure
Volume6
Issue number9
StatePublished - Sep 15 1998

Fingerprint

Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
Catalytic Domain
Inflammation
Crystallography
Protein-Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases
Protein Kinase Inhibitors
Anti-Inflammatory Agents
Phosphotransferases
Adenosine Triphosphate
Binding Sites
Cytokines
Amino Acids
olomoucine
Neoplasms

Keywords

  • CSAID(TM)
  • ERK2
  • Inhibitor
  • MAP kinase
  • Olomoucine
  • p38

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Wang, Z., Canagarajah, B. J., Boehm, J. C., Kassisà, S., Cobb, M. H., Young, P. R., ... Goldsmith, E. J. (1998). Structural basis of inhibitor selectivity in MAP kinases. Structure, 6(9), 1117-1128.

Structural basis of inhibitor selectivity in MAP kinases. / Wang, Zhulun; Canagarajah, Bertram J.; Boehm, Jeffrey C.; Kassisà, Skouki; Cobb, Melanie H.; Young, Peter R.; Abdel-Meguid, Sherin; Adams, Jerry L.; Goldsmith, Elizabeth J.

In: Structure, Vol. 6, No. 9, 15.09.1998, p. 1117-1128.

Research output: Contribution to journalArticle

Wang, Z, Canagarajah, BJ, Boehm, JC, Kassisà, S, Cobb, MH, Young, PR, Abdel-Meguid, S, Adams, JL & Goldsmith, EJ 1998, 'Structural basis of inhibitor selectivity in MAP kinases', Structure, vol. 6, no. 9, pp. 1117-1128.
Wang Z, Canagarajah BJ, Boehm JC, Kassisà S, Cobb MH, Young PR et al. Structural basis of inhibitor selectivity in MAP kinases. Structure. 1998 Sep 15;6(9):1117-1128.
Wang, Zhulun ; Canagarajah, Bertram J. ; Boehm, Jeffrey C. ; Kassisà, Skouki ; Cobb, Melanie H. ; Young, Peter R. ; Abdel-Meguid, Sherin ; Adams, Jerry L. ; Goldsmith, Elizabeth J. / Structural basis of inhibitor selectivity in MAP kinases. In: Structure. 1998 ; Vol. 6, No. 9. pp. 1117-1128.
@article{c0756e3aaaf2484ea651b07accafb0c5,
title = "Structural basis of inhibitor selectivity in MAP kinases",
abstract = "Background: The mitogen-activated protein (MAP) kinases are important signaling molecules that participate in diverse cellular events and are potential targets for intervention in inflammation, cancer, and other diseases. The MAP kinase p38 is responsive to environmental stresses and is involved in the production of cytokines during inflammation. In contrast, the activation of the MAP kinase ERK2 (extracellular-signal-regulated kinase 2) leads to cellular differentiation or proliferation. The anti-inflammatory agent pyridinylimidazole and its analogs (SB [SmithKline Beecham] compounds) are highly potent and selective inhibitors of p38, but not of the closely related ERK2, or other serine/threonine kinases. Although these compounds are known to bind to the ATP-binding site, the origin of the inhibitory specificity toward p38 is not clear. Results: We report the structural basis for the exceptional selectivity of these SB compounds for p38 over ERK2, as determined by comparative crystallography. In addition, structural data on the origin of olomoucine (a better inhibitor of ERK2) selectivity are presented. The crystal structures of four SB compounds in complex with p38 and of one SB compound and olomoucine in complex with ERK2 are presented here. The SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low-activity form of p38. The relatively closed domain structure of ERK2 is able to accommodate the smaller olomoucine. Conclusions: The unique kinase-inhibitor interactions observed in these complexes originate from amino-acid replacements in the active site and replacements distant from the active site that affect the size of the domain interface. This structural information should facilitate the design of better MAP-kinase inhibitors for the treatment of inflammation and other diseases.",
keywords = "CSAID(TM), ERK2, Inhibitor, MAP kinase, Olomoucine, p38",
author = "Zhulun Wang and Canagarajah, {Bertram J.} and Boehm, {Jeffrey C.} and Skouki Kassis{\`a} and Cobb, {Melanie H.} and Young, {Peter R.} and Sherin Abdel-Meguid and Adams, {Jerry L.} and Goldsmith, {Elizabeth J.}",
year = "1998",
month = "9",
day = "15",
language = "English (US)",
volume = "6",
pages = "1117--1128",
journal = "Structure with Folding & design",
issn = "0969-2126",
publisher = "Cell Press",
number = "9",

}

TY - JOUR

T1 - Structural basis of inhibitor selectivity in MAP kinases

AU - Wang, Zhulun

AU - Canagarajah, Bertram J.

AU - Boehm, Jeffrey C.

AU - Kassisà, Skouki

AU - Cobb, Melanie H.

AU - Young, Peter R.

AU - Abdel-Meguid, Sherin

AU - Adams, Jerry L.

AU - Goldsmith, Elizabeth J.

PY - 1998/9/15

Y1 - 1998/9/15

N2 - Background: The mitogen-activated protein (MAP) kinases are important signaling molecules that participate in diverse cellular events and are potential targets for intervention in inflammation, cancer, and other diseases. The MAP kinase p38 is responsive to environmental stresses and is involved in the production of cytokines during inflammation. In contrast, the activation of the MAP kinase ERK2 (extracellular-signal-regulated kinase 2) leads to cellular differentiation or proliferation. The anti-inflammatory agent pyridinylimidazole and its analogs (SB [SmithKline Beecham] compounds) are highly potent and selective inhibitors of p38, but not of the closely related ERK2, or other serine/threonine kinases. Although these compounds are known to bind to the ATP-binding site, the origin of the inhibitory specificity toward p38 is not clear. Results: We report the structural basis for the exceptional selectivity of these SB compounds for p38 over ERK2, as determined by comparative crystallography. In addition, structural data on the origin of olomoucine (a better inhibitor of ERK2) selectivity are presented. The crystal structures of four SB compounds in complex with p38 and of one SB compound and olomoucine in complex with ERK2 are presented here. The SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low-activity form of p38. The relatively closed domain structure of ERK2 is able to accommodate the smaller olomoucine. Conclusions: The unique kinase-inhibitor interactions observed in these complexes originate from amino-acid replacements in the active site and replacements distant from the active site that affect the size of the domain interface. This structural information should facilitate the design of better MAP-kinase inhibitors for the treatment of inflammation and other diseases.

AB - Background: The mitogen-activated protein (MAP) kinases are important signaling molecules that participate in diverse cellular events and are potential targets for intervention in inflammation, cancer, and other diseases. The MAP kinase p38 is responsive to environmental stresses and is involved in the production of cytokines during inflammation. In contrast, the activation of the MAP kinase ERK2 (extracellular-signal-regulated kinase 2) leads to cellular differentiation or proliferation. The anti-inflammatory agent pyridinylimidazole and its analogs (SB [SmithKline Beecham] compounds) are highly potent and selective inhibitors of p38, but not of the closely related ERK2, or other serine/threonine kinases. Although these compounds are known to bind to the ATP-binding site, the origin of the inhibitory specificity toward p38 is not clear. Results: We report the structural basis for the exceptional selectivity of these SB compounds for p38 over ERK2, as determined by comparative crystallography. In addition, structural data on the origin of olomoucine (a better inhibitor of ERK2) selectivity are presented. The crystal structures of four SB compounds in complex with p38 and of one SB compound and olomoucine in complex with ERK2 are presented here. The SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low-activity form of p38. The relatively closed domain structure of ERK2 is able to accommodate the smaller olomoucine. Conclusions: The unique kinase-inhibitor interactions observed in these complexes originate from amino-acid replacements in the active site and replacements distant from the active site that affect the size of the domain interface. This structural information should facilitate the design of better MAP-kinase inhibitors for the treatment of inflammation and other diseases.

KW - CSAID(TM)

KW - ERK2

KW - Inhibitor

KW - MAP kinase

KW - Olomoucine

KW - p38

UR - http://www.scopus.com/inward/record.url?scp=0032530336&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032530336&partnerID=8YFLogxK

M3 - Article

C2 - 9753691

AN - SCOPUS:0032530336

VL - 6

SP - 1117

EP - 1128

JO - Structure with Folding & design

JF - Structure with Folding & design

SN - 0969-2126

IS - 9

ER -