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      Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain

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          Abstract

          Erlotinib and gefitinib, tyrosine kinase inhibitors used to block EGFR (epidermal growth factor receptor) signalling in cancer, are thought to bind only the active conformation of the EGFR-TKD (tyrosine kinase domain). Through parallel computational and crystallographic studies, we show in the present study that erlotinib also binds the inactive EGFR-TKD conformation, which may have significant implications for its use in EGFR-mutated cancers.

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          A small molecule-kinase interaction map for clinical kinase inhibitors.

          Miles Fabian, William Biggs, Daniel Treiber … (2005)
          Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
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            Reduced surface: an efficient way to compute molecular surfaces.

            Jay Olson, Bernd M Sanner, J Spehner (1996)
            Because of their wide use in molecular modeling, methods to compute molecular surfaces have received a lot of interest in recent years. However, most of the proposed algorithms compute the analytical representation of only the solvent-accessible surface. There are a few programs that compute the analytical representation of the solvent-excluded surface, but they often have problems handling singular cases of self-intersecting surfaces and tend to fail on large molecules (more than 10,000 atoms). We describe here a program called MSMS, which is shown to be fast and reliable in computing molecular surfaces. It relies on the use of the reduced surface that is briefly defined here and from which the solvent-accessible and solvent-excluded surfaces are computed. The four algorithms composing MSMS are described and their complexity is analyzed. Special attention is given to the handling of self-intersecting parts of the solvent-excluded surface called singularities. The program has been compared with Connolly's program PQMS [M.L. Connolly (1993) Journal of Molecular Graphics, Vol. 11, pp. 139-141] on a set of 709 molecules taken from the Brookhaven Data Base. MSMS was able to compute topologically correct surfaces for each molecule in the set. Moreover, the actual time spent to compute surfaces is in agreement with the theoretical complexity of the program, which is shown to be O[n log(n)] for n atoms. On a Hewlett-Packard 9000/735 workstation, MSMS takes 0.73 s to produce a triangulated solvent-excluded surface for crambin (1 crn, 46 residues, 327 atoms, 4772 triangles), 4.6 s for thermolysin (3tln, 316 residues, 2437 atoms, 26462 triangles), and 104.53 s for glutamine synthetase (2gls, 5676 residues, 43632 atoms, 476665 triangles).
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              Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor.

              Jennifer L Stamos, Mark Sliwkowski, Charles Eigenbrot (2002)
              The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6-A resolution, both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biochem J
                Journal ID (iso-abbrev): Biochem. J
                Journal ID (pmc): bic
                Journal ID (publisher-id): BJ
                Title: Biochemical Journal
                Publisher: Portland Press Ltd.
                ISSN (Print): 0264-6021
                ISSN (Electronic): 1470-8728
                Publication date (Electronic preprint): 29 October 2012
                Publication date (Electronic): 21 November 2012
                Publication date (Print): 15 December 2012
                Volume: 448
                Issue: Pt 3
                Pages: 417-423
                Affiliations
                *Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
                †Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
                ‡Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
                Author notes

                1These authors contributed equally to this work.

                2Correspondence may be addressed to either of these authors (email mlemmon@ 123456mail.med.upenn.edu or rradhak@ 123456seas.upenn.edu ).

                Co-ordinates and structure factors of the erlotinib-bound EGFR 672–998/V924R structure have been deposited with the PDB under the accession code 4HJO.

                Article
                Publisher ID: BJ20121513
                DOI: 10.1042/BJ20121513
                PMC ID: 3507260
                PubMed ID: 23101586
                SO-VID: 75781840-291c-4443-8ed7-e654a5b2b6ba
                Copyright © © 2012 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 1 October 2012
                Date revision received : 19 October 2012
                Date accepted : 29 October 2012
                Page count
                Figures: 3, Tables: 2, References: 41, Pages: 7
                Categories
                Subject: Accelerated Publication

                ScienceOpen disciplines: Biochemistry
                Keywords: cancer,epidermal growth factor receptor (egfr),erlotinib,gefitinib,inhibitor,molecular dynamics,receptor tyrosine kinase (rtk),x-ray crystallography,dfg, asp-phe-gly,dtt, dithiothreitol,egfr, epidermal growth factor receptor,fep, free energy perturbation,ifd, induced fit docking,md, molecular dynamics,mm/pbsa, molecular mechanics/poisson–boltzmann surface area,nsclc, non-small-cell lung cancer,rmsd, root mean square deviation,sasa, surface-accessible surface area,tkd, tyrosine kinase domain,tki, tyrosine kinase inhibitor
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: cancer, epidermal growth factor receptor (egfr), erlotinib, gefitinib, inhibitor, molecular dynamics, receptor tyrosine kinase (rtk), x-ray crystallography, dfg, asp-phe-gly, dtt, dithiothreitol, egfr, epidermal growth factor receptor, fep, free energy perturbation, ifd, induced fit docking, md, molecular dynamics, mm/pbsa, molecular mechanics/poisson–boltzmann surface area, nsclc, non-small-cell lung cancer, rmsd, root mean square deviation, sasa, surface-accessible surface area, tkd, tyrosine kinase domain, tki, tyrosine kinase inhibitor

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