Prediction of the three-dimensional structure of protein associations with components that undergo conformational deformations and partial re-structuring upon binding is a great challenge. It represents a major bottleneck in the modern structural understanding of biological function and disease. Ensemble docking emerged as a practical approach for incorporating conformational variability of a part of the system. Innovative ways to generate the ensembles using systematic omission scans and/or local relevant normal modes were developed recently by our group and tested in small ligand docking. The methods showed encouraging results in previously unsolvable cases, and are directly transferable to protein docking. In the present proposal, these methods will be extended and applied to protein docking including the most difficult docking of fully unstructured isolated or terminal peptides. Firstly, the conformational ensemble approach will be dramatically accelerated by introducing a new 4D docking procedure in which atomic models with fully flexible parts will be docked in a single run into concurrently present multiple conformation fields. Secondly, a faster and more rigorous all-atom solution refinement protocol will be applied. This protocol operates on softly restrained and fully flexible interface patches. All methods will be tested on a comprehensive induced fit benchmark for protein and peptide interactions that will be made publically available and regularly updated. Finally, the proposed docking protocol will incorporate electron microscopy (EM) data and other experimental restraints. A new damped dynamics flexible fitting method designed for EM fitting will be further developed. The new protein and peptide docking methods and multi domain EM fitting methods will be applied to solving biological problems with collaborating experimental laboratories. Structure prediction of protein and peptide complexes will lead to the discovery and characterization of new sites that can be targeted with small molecule therapeutics.
Prediction of the three-dimensional structure of transient associations of flexible proteins and peptides represents a major bottleneck for modern structural understanding of biological function and disease. We proposed to overcome these major hurdles by using new methods for treating protein flexibility, and apply these methods to discover new targets for the development of molecular therapeutics.
|Ngo, Tony; Kufareva, Irina; Coleman, James L J et al. (2016) Identifying ligands at orphan GPCRs: current status using structure-based approaches. Br J Pharmacol :|
|Kufareva, Irina; Gustavsson, Martin; Holden, Lauren G et al. (2016) Disulfide Trapping for Modeling and Structure Determination of Receptor: Chemokine Complexes. Methods Enzymol 570:389-420|
|Bennett, Brad C; Purdy, Michael D; Baker, Kent A et al. (2016) An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels. Nat Commun 7:8770|
|Wescott, Melanie P; Kufareva, Irina; Paes, Cheryl et al. (2016) Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices. Proc Natl Acad Sci U S A 113:9928-33|
|Aznar, Nicolas; Patel, Arjun; Rohena, Cristina C et al. (2016) AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin. Elife 5:|
|Zheng, Yi; Qin, Ling; ZacarÃas, Natalia V Ortiz et al. (2016) Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540:458-461|
|Leach, Katie; Gregory, Karen J; Kufareva, Irina et al. (2016) Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor. Cell Res 26:574-92|
|Kufareva, Irina (2016) Chemokines and their receptors: insights from molecular modeling and crystallography. Curr Opin Pharmacol 30:27-37|
|O'Hayre, M; Inoue, A; Kufareva, I et al. (2016) Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the GÎ±13/RhoA axis in B cells. Oncogene 35:3771-80|
|Lo, I-Chung; Gupta, Vijay; Midde, Krishna K et al. (2015) Activation of GÎ±i at the Golgi by GIV/Girdin imposes finiteness in Arf1 signaling. Dev Cell 33:189-203|
Showing the most recent 10 out of 82 publications