title: The intrinsic dynamics of enzymes plays a dominant role in determining the structural changes induced upon inhibitor binding.
abstract: The conformational flexibility of target proteins continues to be a major challenge in accurate modeling of protein-inhibitor interactions. A fundamental issue, yet to be clarified, is whether the observed conformational changes are controlled by the protein or induced by the inhibitor. Although the concept of induced fit has been widely adopted for describing the structural changes that accompany ligand binding, there is growing evidence in support of the dominance of proteins' intrinsic dynamics which has been evolutionarily optimized to accommodate its functional interactions. The wealth of structural data for target proteins in the presence of different ligands now permits us to make a critical assessment of the balance between these two effects in selecting the bound forms. We focused on three widely studied drug targets, HIV-1 reverse transcriptase, p38 MAP kinase, and cyclin-dependent kinase 2. A total of 292 structures determined for these enzymes in the presence of different inhibitors and unbound form permitted us to perform an extensive comparative analysis of the conformational space accessed upon ligand binding, and its relation to the intrinsic dynamics before ligand binding as predicted by elastic network model analysis. Our results show that the ligand selects the conformer that best matches its structural and dynamic properties among the conformers intrinsically accessible to the protein in the unliganded form. The results suggest that simple but robust rules encoded in the protein structure play a dominant role in predefining the mechanisms of ligand binding, which may be advantageously exploited in designing inhibitors.
authors.affiliation: Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Bakan
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D000465:Algorithms; D020134:Catalytic Domain; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
references.citation: Curr Opin Struct Biol. 2003 Dec;13(6):748-57
references.pmid: 14675554
references.citation: J Mol Biol. 1999 Apr 16;287(5):821-8
references.pmid: 10222191
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2327-32
references.pmid: 9122194
references.citation: Structure. 2007 Sep;15(9):1040-52
references.pmid: 17850744
references.citation: Curr Opin Struct Biol. 2008 Apr;18(2):178-84
references.pmid: 18302984
references.citation: J Mol Biol. 2004 Mar 12;337(1):209-25
references.pmid: 15001363
references.citation: Curr Opin Struct Biol. 2007 Dec;17(6):633-40
references.pmid: 18024008
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13829-34
references.pmid: 18772387
references.citation: Science. 2006 Apr 14;312(5771):224-8
references.pmid: 16614210
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11182-7
references.pmid: 18678900
references.citation: Protein Eng. 2001 Jan;14(1):1-6
references.pmid: 11287673
references.citation: Biophys J. 2001 Jan;80(1):505-15
references.pmid: 11159421
references.citation: FEBS Lett. 2006 Oct 2;580(22):5130-6
references.pmid: 16962102
references.citation: J Mol Biol. 2009 May 8;388(3):644-58
references.pmid: 19324058
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12730-5
references.pmid: 16129832
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10901-6
references.pmid: 16829580
references.citation: Structure. 2008 Feb;16(2):321-30
references.pmid: 18275822
references.citation: Structure. 2008 May;16(5):736-46
references.pmid: 18462678
references.citation: J Mol Biol. 2000 Aug 25;301(4):1029-39
references.pmid: 10966802
references.citation: J Am Chem Soc. 2005 Jul 6;127(26):9632-40
references.pmid: 15984891
references.citation: Protein Sci. 2007 Jan;16(1):43-51
references.pmid: 17123961
references.citation: Proteins. 2002 Oct 1;49(1):61-70
references.pmid: 12211016
references.citation: Protein Eng. 1999 Sep;12(9):713-20
references.pmid: 10506280
references.citation: J Am Chem Soc. 2005 Dec 14;127(49):17253-60
references.pmid: 16332074
references.citation: Annu Rev Biophys Biomol Struct. 2006;35:115-33
references.pmid: 16689630
references.citation: PLoS Comput Biol. 2008 Apr 11;4(4):e1000060
references.pmid: 18404207
references.citation: Bioinformatics. 2006 Nov 1;22(21):2619-27
references.pmid: 16928735
references.citation: J Med Chem. 2005 Jun 30;48(13):4432-43
references.pmid: 15974595
references.citation: Bioinformatics. 2009 Mar 1;25(5):606-14
references.pmid: 19147661
references.citation: Science. 2008 Jun 13;320(5882):1471-5
references.pmid: 18556554
references.citation: Science. 1992 Jun 26;256(5065):1783-90
references.pmid: 1377403
references.citation: J Med Chem. 2008 Jun 26;51(12):3499-506
references.pmid: 18517186
references.citation: J Am Chem Soc. 2007 Apr 11;129(14):4158-9
references.pmid: 17367145
references.citation: Phys Rev Lett. 2006 Feb 24;96(7):078104
references.pmid: 16606146
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18908-13
references.pmid: 16354836
references.citation: Nature. 2007 Oct 25;449(7165):1078-82
references.pmid: 17960247
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6353-8
references.pmid: 17395714
references.citation: Curr Opin Struct Biol. 1999 Apr;9(2):164-9
references.pmid: 10322205
references.citation: Nat Rev Drug Discov. 2003 Sep;2(9):717-26
references.pmid: 12951578
references.citation: J Mol Biol. 1999 Jan 22;285(3):1023-37
references.pmid: 9887265