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Dynamics of protein-drug interactions inferred from structural ensembles and physics-based models

Bakan, Ahmet (2010) Dynamics of protein-drug interactions inferred from structural ensembles and physics-based models. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The conformational flexibility of target proteins is a major challenge in understanding and modeling protein-drug interactions. A fundamental issue, yet to be clarified, is whether the observed conformational changes are controlled by the protein, or induced by the inhibitor. While 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 as well as 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 prior to ligand binding as predicted by elastic network model analysis. Further, we analyzed NMR ensembles of ubiquitin and calmodulin representing their microseconds range solution dynamics. Our results show that the ligand selects the conformer that best matches its structural and dynamic properties amongst 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 pre-defining the mechanisms of ligand binding, which may be advantageously exploited in designing inhibitors. We apply these lessons to the study of MAP kinase phosphatases (MKPs), which are therapeutically relevant but challenging signaling enzymes. Our study provides insights into the interactions and selectivity of MKP inhibitors and shows how an allosteric inhibition mechanism holds for a recently discovered inhibitor of MKP-3. We also provide evidence for the functional significance of the structure-encoded dynamics of rhodopsin and nicotinic acetylcholine receptor, members of two membrane proteins classes serving as targets for more than 40% of all current FDA approved drugs.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Bakan, Ahmetahb12@pitt.eduAHB12
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairXie, Xiang-Qunxix15@pitt.eduXIX15
Committee MemberChennubhotla, Chakrachakracs@pitt.eduCHAKRACS
Committee MemberLangmead, Christopher
Committee MemberBahar, Ivetbahar@pitt.eduBAHAR
Committee MemberLazo, John Slazo@pitt.eduLAZO
Date: 6 January 2010
Date Type: Completion
Defense Date: 3 December 2009
Approval Date: 6 January 2010
Submission Date: 13 December 2009
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Computational Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: anisotropic network model; collective protein motions; molecular docking; principal component analysis
Other ID:, etd-12132009-205300
Date Deposited: 10 Nov 2011 20:10
Last Modified: 15 Nov 2016 13:54


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