1o4d

File:1o4d.jpg

spinqualitylabelsall models 1o4d, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF SH2 IN COMPLEX WITH RU78262.

OverviewOverview

Results from a novel approach which uses protein crystallography for the, screening of a low affinity inhibitor fragment library are analyzed by, comparing the X-ray structures with bound fragments to the structures with, the corresponding full length inhibitors. The screen for new, phospho-tyrosine mimics binding to the SH2 domain of (pp60)src was, initiated because of the limited cell penetration of phosphates. Fragments, in our library typically had between 6 and 30 atoms and included compounds, which had either millimolar activity in a Biacore assay or were suggested, by the ab initio design program LUDI but had no measurable affinity. All, identified fragments were located in the phospho-tyrosine pocket. The most, promising fragments were successfully used to replace the phospho-tyrosine, and resulted in novel nonpeptidic high affinity inhibitors. The, significant diversity of successful fragments is reflected in the high, flexibility of the phospho-tyrosine pocket. Comparison of the X-ray, structures shows that the presence of the H-bond acceptors and not their, relative position within the pharmacophore are essential for fragment, binding and/or high affinity binding of full length inhibitors. The X-ray, data show that the fragments are recognized by forming a complex H-bond, network within the phospho-tyrosine pocket of SH2. No fragment structure, was found in which this H-bond network was incomplete, and any, uncompensated H-bond within the H-bond network leads to a significant, decrease in the affinity of full length inhibitors. No correlation between, affinity and fragment binding was found for these polar fragments and, hence affinity-based screening would have overlooked some interesting, starting points for inhibitor design. In contrast, we were unable to, identify electron density for hydrophobic fragments, confirming that, hydrophobic interactions are important for inhibitor affinity but of minor, importance for ligand recognition. Our results suggest that a screening, approach using protein crystallography is particularly useful to identify, universal fragments for the conserved hydrophilic recognition sites found, in target families such as SH2 domains, phosphatases, kinases, proteases, and esterases.

DiseaseDisease

Known disease associated with this structure: Colon cancer, advanced OMIM:[190090]

About this StructureAbout this Structure

1O4D is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.

ReferenceReference

Requirements for specific binding of low affinity inhibitor fragments to the SH2 domain of (pp60)Src are identical to those for high affinity binding of full length inhibitors., Lange G, Lesuisse D, Deprez P, Schoot B, Loenze P, Benard D, Marquette JP, Broto P, Sarubbi E, Mandine E, J Med Chem. 2003 Nov 20;46(24):5184-95. PMID:14613321

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