This strategy provides a way to improve a lattice without altering the protein target. To obtain structural information of improved accuracy, we test a strategy involving the lattice-based engineering of crystallization chaperones. In both cases, the resolution was only 3.8 Å, and there was uncertainty in the positioning of small-molecule atoms and in the definition of side-chain interactions. 18), the prototype small molecule for this class of compounds, in the same Env-35O22-PGT122 lattice. We also reported the structure of BMS-378806 (ref. ![]() ![]() We recently reported the structure of BMS-626529 (temsavir) in complex with an HIV-1 Env trimer bound by crystallization chaperones comprising the antigen-binding fragments (Fabs) of antibodies 35O22 and PGT122 (ref. However, both of these strategies can inadvertently introduce modifications that change the properties of protein targets and even their structures 15, 16.Ĭrystallization chaperones, such as antibody fragments, have also been used to facilitate formation of crystal lattice contacts for difficult protein targets 17. Crystal engineering 13, 14 represents an alternative strategy for crystal improvement, whereby inspection of a lattice with poor diffraction identifies weak lattice contacts, which can then be altered through structure-based design. However, structure-based drug design can only be reliably carried out with crystals that diffract with resolution sufficient to provide accurate structural models unfortunately, this resolution prerequisite has been difficult to achieve for many drug targets, even with extensive screening of crystallization conditions and protein variants 12. X-ray crystallography is often instrumental in determining drug-binding mode and in facilitating structure-based drug design 9, 10, 11. We note that these qualities may be related for example, increasing the potency of an inhibitor can be an effective way to counter drug resistance 7, as resistance mutations generally have only incremental effects on the dose−response of a drug 8. Notwithstanding its advanced development and novel mode of action, next-generation inhibitors of fostemsavir have been sought to improve ADME (absorption, metabolism, distribution and elimination) profile 5, to overcome expected drug resistance 6, and to increase potency. Entry inhibitors targeting the gp120 subunit have been developed 3, with a promising small-molecule lead, fostemsavir, the prodrug version of BMS-626529 (temsavir) currently in phase III clinical trials 4. Viral entry is mediated by the HIV-1 envelope (Env) glycoprotein trimer, a type 1 fusion machine comprised of three gp120 subunits and three noncovalently linked gp41 subunits, which binds to cell-surface receptors and fuses viral and host cell membranes 2. 1.2.The entry of HIV-1 into target cells is a critical event in the viral life cycle and a target for drug development 1. Economou The Physics of Solids Springer 2010 (ch 3.3.1) Simon Oxford Solid State Basics Oxford 2013 (p. Kittel Einführung in die Festkörperphysik Oldenbourg 2006 (p- 4) Economou The Physics of Solids Springer 2010 (ch. Marx Festkörperphysik De Gruyter 2014 (ch. Evarestov Quantum Chemistry of Solids Springer 2012 (ch. Usually the basis consists of an atom, a group of atoms or a molecule.įor many solids it is a good approximation to look at them as crystals since they consist of small groups of atoms that are arranged in a repetitive manner. ![]() This generates a structure that is referred to as a crystal: Ī crystal is defined as a lattice with a basis added to each lattice site. Now one could go ahead and replace the lattice points by more complex objects (called basis), e.g. But this is just a matter of taste, so don't let yourself be confused by this! ĭue to our definition the corners of a honeycomb are regarded as a lattice as well, but not as a Bravais lattice. However, objects such as a honeycomb would then not be regarded as a lattice. If one considers for instance the vector space $\mathbb is indeed more correct from a mathematical point of view and even more common among crystallographers. In solid state physics one usually encounters lattices which exhibit a discrete translational symmetry. This is however important in order to establish a language and avoid obscurities when talking about crystal structures.Ī lattice is in general defined as a discrete but infinite regular arrangement of points ( lattice sites) in a vector space Bravais Lattice This article is a bit technical in a sense that it provides mainly definitions of terms and concepts.
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