Drug targets, Protein Structures and Crystallography
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1 Drug targets, Protein Structures and Crystallography NS5B viral RNA polymerase (RNA dep) Hepa88s C drug Sofosbuvir (Sovaldi) FDA 2013 Epclusa - combina8on with Velpatasvir approved in in 2016) Prodrug dependent on the viral
2 Waves An X-ray picture (radiograph), taken by Wilhelm Röntgen in 1896, of Albert von Kölliker's hand. Wilhelm Röntgen Waves and diffraction X-rays: single crystals to 3D electron density Bragg s condition (2dsinθ=nλ ) Unit cell, asymmetric unit, non-crys. symmetry
3 From Crystal to Atomic Model Make a crystal of the drug or drug-target complex Generate a set of X-ray diffrac8on data (synchrotron) Each spot needs: 3 coordinates, h,k,l, intensity and phase, F hkl, A hkl To get the electron density map the Fourier transforma8on is used We need spot intensi8es and phases, but we only have intensi8es. Yet another limita8on of quality Direct methods Anomalous diffraction (MAD) molecular replacement
4 Drug Targets in Uniprot & PDB Uniprot contains ~20,130 human proteins, with the mean length of 550 and median of 400 amino acids PDB contains structures of some DOMAINS of only 6000 of those proteins 30% of protein coverage, 12% amino acid coverage Es8mated number of druggable targets: ~4500 Many drug targets in PDB
5 Protein Data Bank (PDB), 2017 ~126,000 structures ~ 30 % of partial coverage of human proteins 12% coverage by sequence 83% Xray crystallography 8% Nuclear Magnetic Resonance Crystallographic density is a star8ng point. unresolved parts and errors unknown conforma8onal/func8onal states and transient interac8on sites unsolved proteins: low gene and domain coverage of the proteome: 35/800 GPCRs, ~30/50 nuclear receptor LBD; <1/2 of 518 kinases large transient complexes, membrane proteins are problema8c
6 PDB FILE FORMAT HEADER EXTRACELLULAR MATRIX 22-JAN-98 1A3I TITLE X-RAY CRYSTALLOGRAPHIC DETERMINATION OF A COLLAGEN-LIKE TITLE 2 PEPTIDE WITH THE REPEATING SEQUENCE (PRO-PRO-GLY)... EXPDTA X-RAY DIFFRACTION AUTHOR R.Z.KRAMER,L.VITAGLIANO,J.BELLA,R.BERISIO,L.MAZZARELLA, AUTHOR 2 B.BRODSKY,A.ZAGARI,H.M.BERMAN... REMARK 350 BIOMOLECULE: 1 REMARK 350 APPLY THE FOLLOWING TO CHAINS: A, B, C REMARK 350 BIOMT REMARK 350 BIOMT SEQRES 1 A 9 PRO PRO GLY PRO PRO GLY PRO PRO GLY SEQRES 1 B 6 PRO PRO GLY PRO PRO GLY SEQRES 1 C 6 PRO PRO GLY PRO PRO GLY... ATOM 1 N PRO A N ATOM 2 CA PRO A C ATOM 3 C PRO A C ATOM 4 O PRO A O ATOM 5 CB PRO A C... HETATM 130 C ACY C HETATM 131 O ACY O HETATM 132 OXT ACY O Each atom has X, Y, Z, O, B Occupancy B-factor, - smeared atoms (10 to 100+) Occupancy (1. or less) Asymmetric Unit Model, Construct and Biological sequence
7 Biological Sequence, Crystalliza8on Construct and 3D model: differences
8 Difficult cases for crystallography Membrane proteins: only ten GPCRs out of a thousand human ones Fibrils (tubulin, miosin, actin filaments, amyloid) Large particles: ribosomes Flexible multi-domain proteins
9 Unit Cells and Translations Crystals are regular periodic arrays Unit cell is the smallest volume from which the entire crystal can be constructed by translation only Each unit cell contains one or several Asymmetric Units related by crystallographic symmetry (e.g. a mirror plane or a 2-fold rotation axis) a b Unit Cell
10 Unit Cell and Asymmetric Unit One unit cell may contain elements of crystallographic symmetry
11 Asymmetric Unit Asymmetric Unit is the smallest volume from which the unit cell can be constructed by application of the crystallographic symmetry.
12 Asymmetric unit is not unique Two steps: AU is multiplied by the symmetry elements of the cell (unique for each of 230 space groups) Result is translated in 3D
13 Unit Cell and Asymmetric Unit The Unit cell here is one card since by parallel TRANSLATION only the space can be filled The Asymmetric Unit is half a card, related to another half by ROTATION. There are many ways to define that half however. In protein crystals AU does not break proteins Better choice of AU Legal, but poor choice of AU
14 Symmetry operators Translation, rotation, screw rotations, reflection (m), glide reflections. Leaves the object unchanged Screw: rotation + translation by a fraction of a cell dimension 4-fold Proper Rotations Symbol (n) Screw Rotations Symbol (nm) Two-fold Three-fold Four-fold Six-fold , 32 41, 42, 43 61, 62, 63, 64, 65
15 Non-crystallographic symmetry (NCS) An asymmetric unit may still contain several identical molecules or groups of molecules related by LOCAL symmetry Example: a crystal of viral particles, each virus consists of 60 groups of envelope proteins related by local NCS
16 Space Groups 17 groups in 2D 2D group example: p2 230 groups in 3D The most frequent: P P C P C P P1 P2 1
17 Symmetry Group: P Many biomolecules crystallize in P group It has 4 asymmetric units in a unit cell
18 Reconstructing the biological structure from the asymmetric unit You mostly see parts of a biological complex In many cases the asymmetric unit contains MULTIPLE copies of the protein of interest Biological protein a part of a biological assembly (oligomer, homo- or hetero-, a complex,..) A structural domain of interest 1,2,.. domains may form an asymmetric unit via NCS Several asymmetric units form a unit cell Unit cells fill space via translation to form a crystal If you are lucky, your space group will be P1 (no internal symmetry), and the asymmetric unit will consist of only your protein
19 Unit Cell Example Transthyretin binds drugs, transports thyroxine (T4). 2flm (1.65A) TTR Amyloid: Familial amyloid polyneuropathy (or cardiomyopathy) Space group P
20 In P there are four dimers in unit cell The biological unit is a HOMOTETRAMER
21 UNLs (unrecognized ligands) From electron density of a protein drug complex to a full atom model Ambiguities and gaps Hydrogens are invisible Missing/unclear ligand density Missing/amb. loop or side chains Rotations of Asn, Gln Crystallographic and non-crystallographic symmetry, bio-molecule, water, UNLs Fantasy Heavy Atoms Wrong atoms with full occupancy and low B- factors Protonation and Tautomerization ε and δ Histidines, His rotations, and ligand tautomers protons in His, Asp, Glu,Arg, Lys, Cys Protonation and tautomerization of the ligand 2o5r 2gb 3
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