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A crystal form of PSMD10Gankyrin with channels accessible to small molecules


Affiliations
1 Protein Interactome Laboratory for Structural and Functional Biology, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai 412 100, India; and Homi Bhabha National Institute, 2nd Floor, BARC Training School Complex, Anushaktinagar, Mumbai 400 094, India
 

New crystal forms and conditions that aid in rapid formation of crystals would ease the efforts in drug discovery. In addition, if such new crystal forms also yielded high-resolution protein structures, then they can become better templates for screening of drugs using computational tools with better outcome. Such structures are also essential for unambiguous determination of side-chain positions such that subtle conformational changes attributed to mutations, protein dynamics and interactions are true to the proposed mechanism. In this study, we have identified a buffer cocktail which enables crystallization of PSMD10Gankyrin in a novel crystal form. PSMD10Gankyrin is important in the biology of the proteasome assembly and functions of the ubiquitin proteasome pathway. It is also a sought-after therapeutic oncoprotein in multiple cancers. This crystal form yielded a high-resolution structure of PSMD10Gankyrin solved at 1.71 Å. The protein in the crystal is relatively less densely packed with its symmetry-related neighbours. Channels seen all around the protein would guide soaked small molecules to the exposed binding sites. We show that the Alphafold predicted model can be used as an molecular replacement ensemble to solve structures. We also highlight the differences bet­ween the current structure and the Alphafold structure. Thus, the crystal form of PSMD10Gankyrin provides novel insights and opportunities for drug discovery.

Keywords

Crystal forms, drug discovery, protein structures, small molecules.
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  • A crystal form of PSMD10Gankyrin with channels accessible to small molecules

Abstract Views: 300  |  PDF Views: 134

Authors

M. G. Mukund Sudharsan
Protein Interactome Laboratory for Structural and Functional Biology, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai 412 100, India; and Homi Bhabha National Institute, 2nd Floor, BARC Training School Complex, Anushaktinagar, Mumbai 400 094, India
Prasanna Venkatraman
Protein Interactome Laboratory for Structural and Functional Biology, Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai 412 100, India; and Homi Bhabha National Institute, 2nd Floor, BARC Training School Complex, Anushaktinagar, Mumbai 400 094, India

Abstract


New crystal forms and conditions that aid in rapid formation of crystals would ease the efforts in drug discovery. In addition, if such new crystal forms also yielded high-resolution protein structures, then they can become better templates for screening of drugs using computational tools with better outcome. Such structures are also essential for unambiguous determination of side-chain positions such that subtle conformational changes attributed to mutations, protein dynamics and interactions are true to the proposed mechanism. In this study, we have identified a buffer cocktail which enables crystallization of PSMD10Gankyrin in a novel crystal form. PSMD10Gankyrin is important in the biology of the proteasome assembly and functions of the ubiquitin proteasome pathway. It is also a sought-after therapeutic oncoprotein in multiple cancers. This crystal form yielded a high-resolution structure of PSMD10Gankyrin solved at 1.71 Å. The protein in the crystal is relatively less densely packed with its symmetry-related neighbours. Channels seen all around the protein would guide soaked small molecules to the exposed binding sites. We show that the Alphafold predicted model can be used as an molecular replacement ensemble to solve structures. We also highlight the differences bet­ween the current structure and the Alphafold structure. Thus, the crystal form of PSMD10Gankyrin provides novel insights and opportunities for drug discovery.

Keywords


Crystal forms, drug discovery, protein structures, small molecules.

References





DOI: https://doi.org/10.18520/cs%2Fv122%2Fi6%2F674-681