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PDBsum entry 2cfv

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Hydrolase PDB id
2cfv
Jmol
Contents
Protein chain
268 a.a.
Metals
_NI ×4
_CL
Waters ×25

References listed in PDB file
Key reference
Title Large-Scale structural analysis of the classical human protein tyrosine phosphatome.
Authors A.J.Barr, E.Ugochukwu, W.H.Lee, O.N.King, P.Filippakopoulos, I.Alfano, P.Savitsky, N.A.Burgess-Brown, S.Müller, S.Knapp.
Ref. Cell, 2009, 136, 352-363. [DOI no: 10.1016/j.cell.2008.11.038]
PubMed id 19167335
Abstract
Protein tyrosine phosphatases (PTPs) play a critical role in regulating cellular functions by selectively dephosphorylating their substrates. Here we present 22 human PTP crystal structures that, together with prior structural knowledge, enable a comprehensive analysis of the classical PTP family. Despite their largely conserved fold, surface properties of PTPs are strikingly diverse. A potential secondary substrate-binding pocket is frequently found in phosphatases, and this has implications for both substrate recognition and development of selective inhibitors. Structural comparison identified four diverse catalytic loop (WPD) conformations and suggested a mechanism for loop closure. Enzymatic assays revealed vast differences in PTP catalytic activity and identified PTPD1, PTPD2, and HDPTP as catalytically inert protein phosphatases. We propose a "head-to-toe" dimerization model for RPTPgamma/zeta that is distinct from the "inhibitory wedge" model and that provides a molecular basis for inhibitory regulation. This phosphatome resource gives an expanded insight into intrafamily PTP diversity, catalytic activity, substrate recognition, and autoregulatory self-association.
Figure 3.
Figure 3. Novel Conformations and Movement of the Catalytic (WPD) Loop
(A) WPD loop conformations are shown by a PTP representative of each state: closed (blue, PTP1B, PDB: 1SUG); open (yellow, PTP1B, PDB: 2HNP); and atypical (magenta, GLEPP1, PDB: 2GJT; STEP, PDB: 2BIJ; Lyp, PDB: 2P6X). The intermediate WPD loop conformation of PCPTP1 (PDB: 2A8B) is not shown for clarity. Other PTP structures are shown with a thin transparent line tracing the backbone and are colored according to conformation.
(B) Superimposition of the structure of STEP-C/S in complex with pY (PDB: 2CJZ; gray) and the apo STEP (PDB: 2BIJ; light green) showing that the WPD loop conformation does not change on substrate binding (pTyr, orange). The catalytic water molecule (Wa) corresponding to that found in closed structures is shown.
(C) Superimposition of the structure of STEP-C/S in complex with pY (PDB: 2CJZ; green) and PTP1B with the insulin receptor peptide (PDB: 1G1H; red). The conserved water molecule found in closed structures is shown: PTP1B (1SUG, yellow); GLEPP1 (2G59, orange); HePTP (2A3K, black), DEP1 (2NZ6, magenta). The arrow indicates the position of the displaced water molecule in STEP-C/S structure.
Figure 4.
Figure 4. Secondary Substrate-Binding Pockets
(A) Two extreme conformations of the second-site loop are shown (orange) from RPTPγ (extended helix) and HEPTP (closed in conformation). The catalytic cysteine is shown in a space-filling CPK representation, and loops are colored as follows: WPD (magenta), β5/β6 loop (green), and gateway (red). The dually pTyr phosphorylated insulin receptor peptide (from PDB: 1G1H) is shown superimposed (for reference only) to indicate the position of the secondary substrate-binding pocket. The positions of Arg24 and gateway residues Met258 and Gly259 of PTP1B are shown in an enlarged view.
(B) Surface topology and electrostatic charge for the active site (pY), gateway region, and secondary pocket (2pY) are shown for each of the five categories with the dually pTyr phosphorylated insulin receptor peptide superimposed.
(C) Representative second-site loop conformations are shown for each category (see also Supplemental Data). Category I: SHP2, BDP1, LYP; Category II: IA2, IA2β; Category III: LAR, RPTPσ; Category IV: PTPH1, MEG1, PTPD2, CD45; Category V: STEP, HEPTP, PCPTP1.
The above figures are reprinted from an Open Access publication published by Cell Press: Cell (2009, 136, 352-363) copyright 2009.
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