publication . Preprint . 2018

The Dynamic Conformational Landscapes of the Protein Methyltransferase SETD8

Anqi Ma; John D. Chodera; Cheng Luo; Kyle A. Beauchamp; Hualiang Jiang; Wenyu Yu; Peter J. Brown; Rafal P. Wiewiora; Minkui Luo; Minkui Luo; ...
Open Access
  • Published: 12 Oct 2018
  • Publisher: Cold Spring Harbor Laboratory
Abstract
<jats:title>Abstract</jats:title><jats:p>Elucidating conformational heterogeneity of proteins is essential for understanding protein functions and developing exogenous ligands for chemical perturbation. While structural biology methods can provide atomic details of static protein structures, these approaches cannot in general resolve less populated, functionally relevant conformations and uncover conformational kinetics. Here we demonstrate a new paradigm for illuminating dynamic conformational landscapes of target proteins. SETD8 (Pr-SET7/SET8/KMT5A) is a biologically relevant protein lysine methyltransferase for <jats:italic>in vivo</jats:italic> monomethylati...
Subjects
free text keywords: Ligand, Structural biology, Biophysics, Enzyme, chemistry.chemical_classification, chemistry, Lysine, Protein structure, Protein dynamics, Histone H4, Mutant
Funded by
NIH| Epigenetic Therapy and Prader-Willi Syndrome
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01HD088626-02
  • Funding stream: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
,
EC| ULTRA-DD
Project
ULTRA-DD
Unrestricted Leveraging of Targets for Research Advancement and Drug Discovery
  • Funder: European Commission (EC)
  • Project Code: 115766
  • Funding stream: FP7 | SP1 | SP1-JTI
,
NSERC
Project
  • Funder: Natural Sciences and Engineering Research Council of Canada (NSERC)
,
NIH| The role of reorganization energy in achieving selective kinase inhibition
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01GM121505-02
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| Targeting Lysine Methyltransferases EZH2 and EZH1 for Treating MLL-rearranged Leukemias
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01CA218600-02
  • Funding stream: NATIONAL CANCER INSTITUTE
45 references, page 1 of 3

McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658-674 (2007).

Schuttelkopf, A. W. et al. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr. 60, 1355-1363 (2004).

Chem. Inf. Comput. Sci. 44, 2133-2144 (2004).

Langer, G. et al. Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7. Nat. Protoc. 3, 1171-1179 (2008).

Perrakis, A. et al. wARP: improvement and extension of crystallographic phases by weighted averaging of multiple-refined dummy atomic models. Acta Crystallogr. D Biol. Crystallogr. 53, 448-455 (1997).

Murshudov, G. N. et al. REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr. D Biol. Crystallogr. 67, 355-367 (2011).

Bricogne G., B. E., Brandl M., Flensburg C., Keller P., Paciorek W., et al. Buster, version 2.10.2.

Emsley, P. et al. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486-501 (2010). [OpenAIRE]

Yang, H. et al. Automated and accurate deposition of structures solved by X-ray diffraction to the Protein Data Bank. Acta Crystallogr. D Biol. Crystallogr. 60, 1833-1839 (2004).

Grochulski, P. et al. Beamline 08ID-1, the prime beamline of the Canadian Macromolecular Crystallography Facility. J. Synchrotron Rad. 18, 681-684 (2011).

Otwinowski, Z. et al. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326 (1997).

Evans, P. Scaling and assessment of data quality. Acta Crystallogr. D Biol. Crystallogr. 62, 72-82 (2006).

Crystallogr. 30, 1022-1025 (1997).

McRee, D. E. XtalView/Xfit--A versatile program for manipulating atomic coordinates and electron density. J. Struct. Biol. 125, 156-165 (1999). [OpenAIRE]

Linscott, J. A. et al. Kinetic isotope effects reveal early transition state of protein lysine methyltransferase SET8. Proc. Natl. Acad. Sci. U S A 113, E8369-E8378 (2016).

45 references, page 1 of 3
Abstract
<jats:title>Abstract</jats:title><jats:p>Elucidating conformational heterogeneity of proteins is essential for understanding protein functions and developing exogenous ligands for chemical perturbation. While structural biology methods can provide atomic details of static protein structures, these approaches cannot in general resolve less populated, functionally relevant conformations and uncover conformational kinetics. Here we demonstrate a new paradigm for illuminating dynamic conformational landscapes of target proteins. SETD8 (Pr-SET7/SET8/KMT5A) is a biologically relevant protein lysine methyltransferase for <jats:italic>in vivo</jats:italic> monomethylati...
Subjects
free text keywords: Ligand, Structural biology, Biophysics, Enzyme, chemistry.chemical_classification, chemistry, Lysine, Protein structure, Protein dynamics, Histone H4, Mutant
Funded by
NIH| Epigenetic Therapy and Prader-Willi Syndrome
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01HD088626-02
  • Funding stream: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
,
EC| ULTRA-DD
Project
ULTRA-DD
Unrestricted Leveraging of Targets for Research Advancement and Drug Discovery
  • Funder: European Commission (EC)
  • Project Code: 115766
  • Funding stream: FP7 | SP1 | SP1-JTI
,
NSERC
Project
  • Funder: Natural Sciences and Engineering Research Council of Canada (NSERC)
,
NIH| The role of reorganization energy in achieving selective kinase inhibition
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01GM121505-02
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| Targeting Lysine Methyltransferases EZH2 and EZH1 for Treating MLL-rearranged Leukemias
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01CA218600-02
  • Funding stream: NATIONAL CANCER INSTITUTE
45 references, page 1 of 3

McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658-674 (2007).

Schuttelkopf, A. W. et al. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr. 60, 1355-1363 (2004).

Chem. Inf. Comput. Sci. 44, 2133-2144 (2004).

Langer, G. et al. Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7. Nat. Protoc. 3, 1171-1179 (2008).

Perrakis, A. et al. wARP: improvement and extension of crystallographic phases by weighted averaging of multiple-refined dummy atomic models. Acta Crystallogr. D Biol. Crystallogr. 53, 448-455 (1997).

Murshudov, G. N. et al. REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr. D Biol. Crystallogr. 67, 355-367 (2011).

Bricogne G., B. E., Brandl M., Flensburg C., Keller P., Paciorek W., et al. Buster, version 2.10.2.

Emsley, P. et al. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486-501 (2010). [OpenAIRE]

Yang, H. et al. Automated and accurate deposition of structures solved by X-ray diffraction to the Protein Data Bank. Acta Crystallogr. D Biol. Crystallogr. 60, 1833-1839 (2004).

Grochulski, P. et al. Beamline 08ID-1, the prime beamline of the Canadian Macromolecular Crystallography Facility. J. Synchrotron Rad. 18, 681-684 (2011).

Otwinowski, Z. et al. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326 (1997).

Evans, P. Scaling and assessment of data quality. Acta Crystallogr. D Biol. Crystallogr. 62, 72-82 (2006).

Crystallogr. 30, 1022-1025 (1997).

McRee, D. E. XtalView/Xfit--A versatile program for manipulating atomic coordinates and electron density. J. Struct. Biol. 125, 156-165 (1999). [OpenAIRE]

Linscott, J. A. et al. Kinetic isotope effects reveal early transition state of protein lysine methyltransferase SET8. Proc. Natl. Acad. Sci. U S A 113, E8369-E8378 (2016).

45 references, page 1 of 3
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